Apparatus, method and computer-readable storage medium for evaluating a physiological condition of a patient

ABSTRACT

A method is provided that includes receiving measurements of biological elements from a blood sample of a patient. The respective biological elements are managed by the endocrine system, which is organizable in axes including a corticotropic axis, gonadotropic axis, thyreotropic axis and somatotropic axis. The method includes calculating a plurality of indexes as functions of the measurements. The indexes reflect physiological relationships between the biological elements and the hormones that manage the respective biological elements, and at least some of the indexes reflect physiological relationships between hormones across axes of the endocrine system. The method also includes evaluating the indexes by axis of the endocrine system to facilitate identification of one or more dysfunctions capable of participating in the genesis, installation and evolution of a pathology, and thereby formulate a diagnosis of the patient. And the method includes administering a therapy to the patient in accordance with the diagnosis.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional Patent Application No. 61/355,959, entitled: Apparatus, Method and Computer-Readable Storage Medium for Evaluating a Patient, filed Jun. 17, 2010, the content of which is hereby incorporated by reference in its entirety.

FIELD

The present invention generally relates to evaluating a physiological condition of a patient, and more particularly, relates to a biological simulation model for evaluating the physiological condition of the patient.

CONTENT

The content of the present application as provided below is broken down in the following sections.

1. Summary

2. Background

3. Brief Description of the Drawings

4. Detailed Description

-   -   4-1. The Integrative Biological Simulation Model     -   4-2. Testing the Biological Simulation Model Model on         Pathologies     -   4-3. Testing the Biological Simulation Model on the Endocrine         System     -   4-4. The Endobiogenic Medical Assistant (EMA™)     -   4-5. Conclusions

5. Claims

6. Abstract

** Attachment: Evaluation Guidelines

1. SUMMARY

Various example embodiments of the present invention may be summarized as follows:

A. A methodology is provided, which is based on an integrative approach of physiological mechanisms which support the functioning of the human body. It utilizes a Biological Simulation Model for evaluating the physiological links existing between specific biological elements measured in blood and their hormonal managers.

It permits to one establish the real state of an organism and to highlight the physiological regular phenomena and their dysfunctions, which participate in the genesis, installation and evolution of the pathology.

An amount of 35 measurements (called indexes) is shown as an illustration, with their rationale and their testing on various pathologies. Also shown is the functioning of the endocrine system through the Biological Simulation Model.

B. A data system, based on the above methodology, referred to herein without loss of generality as the Endobiogenic Medical Assistant (EMA™), is provided to assist the practitioner both on clinical and physiological evaluation, with an automated physiological diagnostic assistant (illustrated in this document) highlighting both the main dysfunctions and their required correcting actions. The therapeutic is also assisted with a menu of recommended treatments on clinical symptomatic findings and physiological actions. A “Walkthrough a Consultation” example is included in the document to illustrate how the system may operate.

The system also serves as a tracking tool to follow up progress on the patient state and verify the validity of the diagnostic and the efficiency of the selected therapy.

2. BACKGROUND

Exemplary embodiments of the present invention provide a Biological Simulation Model and associated apparatus, method and computer-readable storage medium for evaluating a patient (“exemplary” as used herein referring to “serving as an example, instance or illustration”).

Exemplary embodiments of the present invention consider the organism as a whole, made of elements in permanent interaction and working together as a network. It quantifies the physiological relationships at organ and organism-level that drive the functioning of the body, and it helps identify the underlying dysfunctions linked with a disease and their evolution with or without treatment. It goes beyond the symptomatic approach of the disease and takes into account the state of the patient in its overall functioning, the so called “terrain” of the patient, which plays a key role in the ability of an individual to face a disease. For example, exemplary embodiments of the present invention facilitate an understanding of why an individual faced with a very cold weather will contract pneumonia, while similar cold weather had no effect on the individual a year earlier. Similarly, for example, exemplary embodiments of the present invention facilitate an understanding of why out of ten people faced with very cold weather under similar conditions, one will contract sinusitis, two will contract pneumonias, one will contract shingles, the rheumatoid arthritis of one will flare-up, while the other five will not contract anything.

The disease may be viewed not only as caused by a factor X, but may also and primarily be caused by one or more dysfunctions of the organism. In fact, the disease, as may be seen through the symptoms, may be considered the end of an internal process where the body has unsuccessfully attempted to contain the exposure. The symptom may be considered the signal that the body has failed in its attempt, and it will need to mobilize many more resources, unless it gets outside help. The Biological Simulation Model of exemplary embodiments of the present invention facilitates an understanding of what happened and identify the root causes that drove the failure of the organism.

Exemplary embodiments propose an explanation of the basic functioning of the organism, under control of the endocrine system, as the manager of the physiological phenomena that permits the life maintenance within the body, through a sequence of catabolic and anabolic metabolic activities.

Regulation of the internal environment requires a single and autonomous system manager that has the ability to interact permanently with all organs and body systems in order to direct and control all input/output transfers. This system manager also needs the ability to act for its own safeguard in order to remain efficient and manage the organism.

The endocrine system can fulfill the mission of managing the overall organism. The endocrine system is connected to all systems, and may act anywhere in the body and react to all kinds of solicitations: sensorial, metabolic or physiological. The endocrine system is able to reset the basal state (homeostasis) and to participate in its evolution; and it participates in growth, ensures cells nutrition and prioritizes the distribution of energetic resources. The endocrine system manages all factors involved in the defense system of the organism, and manages two fundamental attributes of the organism: short term and long term adaptation, which are hormone-dependent. It also has enough autonomy to correct its own deficiencies.

As an example, in the 1930s, Hans Selye described the role of the endocrine system in the body response to specific aggressions such as third-degree burns, spread-out infections, hemorrhages and the like, which were associated with identical reactions from the organism, which he referred to as the General Adaptation Syndrome (GAS).

Exemplary embodiments propose not only a global view on how the endocrine system organizes the body response to any kind of aggression (external or internal, physical, chemical, viral, emotional, etc.), but also how it manages the maintenance of the basic structure of the organism.

3. BRIEF DESCRIPTION OF THE DRAWINGS

Having thus described the invention in general terms, reference will now be made to the accompanying drawings, which are not necessarily drawn to scale, and wherein:

FIGS. 1-6 are graphs illustrating various data produced according to examples testing a model according to exemplary embodiments of the present invention;

FIG. 7 is a graph of the endocrine system;

FIG. 8 is a graph providing a summary of the catabolic and anabolic activities of the axes of the endocrine system;

FIG. 9 is a schematic block diagram of an apparatus configured to operate in accordance with exemplary embodiments of the present invention;

FIG. 10 is an overall system flow according to various exemplary embodiments of the present invention; and

FIGS. 11-35 illustrate portions of various example displays that may be presented during operation of the system of exemplary embodiments of the present invention.

4. DETAILED DESCRIPTION

The present invention now will be described more fully hereinafter with reference to the accompanying drawings, in which preferred embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like numbers refer to like elements throughout.

4-1. The Integrative Biological Simulation Model

The Biological Simulation Model of exemplary embodiments of the present invention enables measurement of the overall functioning of the organism in its various aspects: endocrine, metabolic and tissular aspects, and enables such measurement at cell, organ and global level, through a series of measurements, called indexes. Through these indexes, the Biological Simulation Model may facilitate a better understanding of the physiological functioning of the organism, identifying its pathological tendencies, and/or determining of the imbalances that may be the root causes of a pathology. The Biological Simulation Model also facilitates tracking the evolution of the organism and the risks for relapses, following the efficiency of treatment, and/or identifying the side effects of a medication.

The indexes are calculated from data obtained from a single, inexpensive blood draw, and many of the indexes are based on only two to three variables, along physiological relationships identified in published research work. The simplicity of the selection is an essential factor to ensure reliability of the norms and reproducibility across patients, under similar terrain conditions, whether they are pathologic or not. The consistency with a global view of the endocrine system is achieved by defining indexes, which are mostly relative indexes, i.e., indexes which are functions of other indexes, which represent over 80% of all indexes.

An index is designed by first defining what is to be evaluated, such as a level of activity (usually relative), a yield, or a circulating rate. Relevant parameters affecting the index are then identified and selected, which parameters will be used as variables in the formulaic representation of the index. These parameters are data obtained from the blood draw, other indexes or some combination of both. Various indexes are in the form of a ratio, and in such instances, the parameters may appear in the numerator (the index “varies like”) or denominator (the index “varies like the reverse”) of the ratio, like in the basic formulas of physical science.

If it is desirable to differentiate the weight of two or more parameters on the same level (numerator or denominator), a mathematical differentiator may be introduced, such as a square or cubed function. Additionally, a digit number may be added, such as to maintain the index in the same band than other similar indexes. One of the objectives in the design of the indexes is to capture the relevant parameters and to select a set of formulas fully consistent with each other.

It should be noted that the indexes are designed bottom-up, born from proved physiological relationships and tested through clinical evaluation. For this reason, as well as the complexity of the human organism, there is no global index, because it would not satisfy the criteria of reliability and reproducibility.

Exemplary embodiments of the present invention also provide an apparatus and computer-readable storage medium that may assist a user in their diagnostic evaluation of a patient and in the selection of an appropriate therapy. Although exemplary embodiments of the present invention contemplate a large number of indexes, the following present examples of a number of indexes (both direct and indirect).

Blood draw (sample) data (19 data, of which 16 are used by the system):

red cells, leucocytes and their distribution (neutrophils through monocytes)

haemoglobin and platelets count

LDH (Lactate dehydrogenase), CPK (creatine phosphokinase) and TSH (thyroid stimulating hormone)

osteocalcin, alkaline phosphatases and their isoenzymes (hepatic, bone, intestine)

potassium and calcium

Examples of Indexes

1. The genital ratio measures the relative tissular activity of androgens versus estrogens, and is defined as follows: Genital Ratio=Red cells/(Leukocytes×10³).

Red cells synthesis is primarily caused by androgens, which are stimulated by the luteinizing hormone (LH) from the anterior pituitary. Leucocytes, on the other hand, are under the influence of estrogens, which are stimulated by the follicle-stimulating hormone (FSH). Thus, the ratio of red cell to white cell counts (Red cells/White cells) is referred to as the genital ratio and is equal to the ratio of LH/FSH. The 10³ factor is required to adjust both the numerator and the denominator to the same units, such as when the red cells are expressed in millions units/mm³, and white cells are expressed in thousands units/mm³.

** Publications:

a. Androgens—Red cells:

M. Alen, Androgenic Steroid Effects on Liver and Red Cells, BJ Sports Medicine, vol. 19(1), pp 15-20, March 1985.

N Hara et al., Decline of the Red Blood Cells Count in Patients Receiving Androgen Deprivation Therapy for Localized Prostate Cancer, Division of Urology, Dept of Regenerative and Transplant Medicine, Niigata University, Niigata, Japan, Urology, vol. 75, issue 6, pp. 1441-45, June 2010.

b. Estrogens—Leukocytes:

R. C. Crafts M.D., Effects of Estrogens on the Bone Marrow of Adult Female Dogs, Dept of Anatomy, Boston University School of Medicine, Boston, Mass., USA, American Society of Haematology, Blood 1948 vol. 3, pp 276-285.

Y Zheng et al., Immuno-Histochemical Characterization of the Estrogens-Stimulated Leucocytes Influx in the Immature Rat Uterus, Dept of Obstetrics and Gynecology, Division of Reproductive Biology, The University of Pennsylvania Medical School, Philadelphia, USA Journal of Leucocyte Biology, vol. 44, pp 27-32 (1988).

2. The genito-thyroid (GT) index measures the thyroid response to the estrogenic demand, and is defined as follows: Genito-Thyroid Ratio Index=Neutrophils/Lymphocytes, both variables of which may be expressed in percentages. The granulocytes secretion (neutrophils represent 90% of granulocytes which include neutrophils, eosinophils and basophils) is typically under the influence of estrogens, while the lymphocytes are under TSH influence. Thus, the ratio of neutrophils to lymphocytes represents the thyroid response to the estrogenic demand, and not the reverse.

The paradox here comes from the TSH which is the upper level stimulation of the thyroid and usually varies like the reverse of the thyroid activity. If TSH is medium to low, the thyroid is usually strong, and vice versa; if the TSH is medium to high, the thyroid response to the estrogenic demand is usually low.

** Publications:

a. Estrogens—Neutrophils (Granulocytes):

R. C. Crafts M.D., Effects of Estrogens on Number of Neutrophils in Bone Marrow of Adult Female Dogs, Dept of Anatomy, Boston university School of Medicine, Boston, Mass. U.S.A., American Society of Hematology Blood vol. 3 N^(o) 3, pp 276-285 (1948).

S. A. Robertson et al., Ovarian Steroid Hormones Regulate Granulocyte Macrophage Colony, Dept of Obstetrics and Gynecology, University of Adelaide, South Australia, PubMed PUBMI 8838016.

Notably the R. C. Crafts publication is the same as indicated above as Neutrophils are part of the Leucocytes (or White Cells). The summary of the publication in fact reads as follows: “Large doses of estrogens have a profound effect on the bone marrow of adult dogs. The initial reaction is a great increase in the number of Neutrophilic elements in the bone marrow. These neutrophils are released into the blood stream, causing a marked rise in the total white cells count.”

b. Lymphocytes—TSH:

T. Mukuta et al., Activation of T Lymphocyte Subsets by Synthetic TSH Receptor, Dept of Medicine, Wellesley Hospital, University of Toronto, Ontario, Canada, Journal Clinical Endocrinol. Metab. 80 (4), pp. 1264-72 (April 1995).

3. The adaptation ratio measures the relative activity of the ACTH hormone in its adaptative function relative to FSH, and is defined as Adaptation Ratio=Eosinophils//Monocytes=ACTH//FSH.

Under stimulation of ACTH, glucocorticoids (cortisol) reduce the circulating rate of eosinophils through sequestration in the spleen and the lungs (Thorn test). Conversely, an increase of eosinophils, a characteristic of a congestion phase, will indicate a shortage of glucocorticoids, hence an elevation of the upper level stimulating hormone, the ACTH. The eosinophils will vary like ACTH.

The monocytes are depending on the estrogenic response to a FSH stimulation, and are inhibited by estrogens, hence the lower are estrogens the higher are monocytes and FSH, and the monocytes will vary like FSH.

The initial physiological link of the General Adaptation Syndrome is thus characterized by the link between ACTH and FSH.

By definition, the ratio eosinophils//monocytes will be called Adaptation Ratio and it will be equal to ACTH//FSH, representing the response of FSH to ACTH. Adaptation Ratio represents both the level of the aggression and the response of the organism to the aggression: the lower is the adaptation index, the higher is the aggression and usually the higher is the glucocorticoid response (cortisol) generating a sharp reduction of eosinophils, consistent with a low adaptation ratio.

** Publications:

N. Sabag et al., Cortisol-Induced Migration of Eosinophils to Lymphoid Organs, Laboratory of Experimental Endocrinology, Department of Experimental Morphology, University of Chile Medical School, Santiago Norte, Casilla 21104, Correo 21, Santiago, Chile, Cellular and Molecular Life Sciences, vol. 34, no. 5, pp. 666-67, May 1978.

R. R. de Mowbray et al., ACTH in Diagnosis of Adrenal Insufficiency (THORN Test), Guy's hospital and Chelsea Hospital for Women, U.K., British Medical Journal, vol. 1 (4800) pp 17-21 (January 1953).

H. Selye, The General Adaptation and the Diseases of Adaptation, Journal of Clinical Endocrinology & Metabolism, vol. 6, no. 2, pp. 117-230 (1946).

M. A. Giembycz et al., Pharmacology of the Eosinophils, Imperial College School of Medicine at the National Heart and Lung Institute, London, U.K., Pharmacological Reviews, vol. 51, no. 2, pp 213-340.

J. E. Cox & F. H. A. Mohamed, Studies of Pituitary-Adrenal-Testis Interaction in Sheep. II The Effects of Repeated Injections Of Adrenocorticotrophic Hormone Outside The Breeding Season, Division of Equine Studies and Farm Animal Surgery Department of Veterinary Clinical Science University of Liverpool Veterinary Field Station Leahurst, Neston, South Wirral, L64 7TE, U.K., Therionology (1988) April; 29(4): pp. 867-72.

4. The starter index measures the relative activity of glucagon versus adrenaline and is defined as follows: Starter index=Leucocytes mobilization/Platelets mobilization.

Notably, the normal reaction to a stress situation is an adrenaline discharge via the beta sympathetic. It is the General Adaptation Syndrome which blocks the cell access to energy except in sensitive areas such as brain and heart, which need extra energy. It is the so-called immediate mobilization which distributes energy where it is most needed. At the end of the aggression, an insulin discharge will drive back to the original state (homeostasis).

When the organism is faced with a lasting or chronic aggression, it will choose the glucagon route via the alpha sympathetic along the stimulation path alpha→CRF→TRH→pancreas→glucagon, with glucose discharge which will increase glycemia, generating an increase in metabolism. It is so called mediate mobilization, which is an anticipation over the General Adaptation Syndrome. In a situation of pathologic aggression, the organism will always choose the glucagon route to increase its energy reserves.

The mobilization of the leucocytes out of the splanchnic reserve will be triggered via the alpha sympathetic→glucagon route, while the platelets mobilization out the splanchnic reserve will be triggered via the beta sympathetic→adrenaline route, hence the starter definition to measure the relative activity of glucagon versus adrenaline.

5. The Cata-Ana index measures the relative part of the catabolic activity versus the anabolic activity of the organism, and represents the mobilization of factors participating in the set up of the immediate defense system, within the general adaptation syndrome. The Cata-Ana index is defined as Cata-Ana Index=Genito-thyroid Ratio/Genital Ratio×Starter index.

The genito-thyroid index represents the catabolic response of the thyroid to the anabolic estrogenic demand during the general adaptation syndrome. The Cata-Ana index varies like the Genito-thyroid ratio.

The Genital ratio tends to decrease in case of an aggression, by the mobilization of leucocytes and acts as an amplifying factor, while the Starter, depending whether the response is an adrenaline driven defense (immediate mobilization) or a glucagon driven defense (mediate aggression) will be an amplification factor or a moderating factor. In case of a pathologic aggression, a higher starter will tend to reduce the cata-ana in relative terms since the glucagon route may assist the glucocorticoide response. The Cata-Ana index will vary like the reverse of the Genital ratio and the Starter index.

The product Genital Ratio×Starter index, is also defined as the Adjusted Genital ratio and it measures the Genital ratio, when excluding the effect of adaptation.

6. The cortisol index measures the cortisol activity of the adrenal gland and its excretion during the adaptation syndrome, and is defined as follows: Cortisol Index=Cata-Ana Index/Adaptation Ratio.

As indicated above, the Cata-Ana index measures the relative catabolic versus anabolic activity and represents the initial response to an aggression. The cortisol activity will vary like the Cata-Ana index.

As also indicated above, the adaptation ratio equals the ACTH/FSH ratio. ACTH is the stimulating hormone of the cortisol, and hence, ACTH varies like the reverse of cortisol. That is, the lower the ACTH, the lower the adaptation ratio and the higher the cortisol activity. The Cortisol index will vary like the reverse of the adaptation ratio

Consequently the cortisol index varies like the Cata-Ana index and like the reverse of the adaptation ratio.

7. The adrenal gland index measures the activity of the adrenal gland, which has two types of activities, namely, an adaptive activity to respond to the aggression, and a permissive activity to support the aromatization of adrenal androgens into estrogens.

The adrenal gland index is defined as:

Adrenal Gland Index=Cata-Ana Index/Genital Ratio.

In this regard, below are 2 different points to explain how the index was built:

The Cata-Ana index measures the mobilization of factors participating in the set up of the immediate defense system within the general adaptation syndrome, and hence, adrenal gland activity varies like the Cata-Ana index.

The lower the genital ratio, the stronger the estrogenic activity and the higher the permissive demand for additional aromatization from the adrenal gland activity, and hence, the adrenal gland index varies like the reverse of the genital ratio.

8. The histamine index measures the activity of histamine, an amino substance available in most tissues (particularly in lungs and liver), which triggers capillary dilatation and increases secretory activity. The histamine index is defined as follows: Histamine Index=(Eosinophils×Platelets×Genital Ratio)/Cortisol Index.

In the representation of the histamine index, the cortisol index and eosinophils vary in reverse to one another and tend to amplify histamine when cortisol decreases (hence eosinophils increase), and reduce histamine when cortisol increases (hence eosinophils decrease).

Platelets amplify the capillary dilatation (as histamine does) by their role on blood coagulation, and hence, histamine varies like platelets. And an increase in the genital ratio reflects a higher solicitation of androgens, which may increase histamine, and hence, histamine varies like the genital ratio.

** Publications:

R. W. Schayer et al., Binding of Histamine in Vitro and its Inhibition by Cortisone, Rheumatic Fever Research Institute, Northwestern University, Medical School, Chicago, Ill., USA, Am J Physiology (September 1956) vol. 187, no. 1, pp. 63-65.

A. P. Lima et al., Effects of Castration and Testosterone Replacement on Peritoneal Histamine Concentration and Lung Histamine Concentration in Pubertal Male Rats, Depts of Physiology and Morphology, Faculties of Medicine and Odontology of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil, Journal of Endocrinology (2000), vol. 167, no. 1, pp. 71-75.

9. The adaptogen index measures the type of adaptation used by the organism, and is defined by the ratio of potassium to calcium, i.e., Adaptogen Index=K/Ca.

In situations of acute stress, using the general adaptation syndrome, there is a slight increase of Calcium and a limited change in Potassium, in terms of blood content: the adaptogen index will experience a slight reduction, which will not last.

In situations of repetitive stress, on the other hand, the aldosterone will be solicited and it will trigger a reduction of Potassium, hence a decrease in the adaptogen index (K//Ca ratio).

The adaptation short cut, using beta-endorphins, will not use aldosterone, and will maintain or eventually increase the blood content of Potassium, while the Calcium blood rate will be reduced by glucocorticoids: as a consequence, the adaptogen index (K//Ca ratio) will increase.

10. The βMSH/αMSH ratio index is defined as follows: βMSH/αMSH Index=Thyroid Metabolic Index/Adaptogen Index.

Beta-MSH (βMSH) and alpha-MSH (αMSH) are melanocyte-stimulating hormones produced in the intermediate lobe of the pituitary gland and are used for reactivating the adrenal gland by increasing the number of ACTH receptors and triggering their sensitivity. They are two complementary ways to stimulate ACTH:

a. The regular cortisol regulation is done through the ACTH-cortisol route, hence βMSH and an adrenaline discharge triggered by the beta sympathetic.

b. While the required surplus in cortisol is obtained through the αMSH route, e.g., if cortisol activity is insufficient, the αMSH route will be used in greater proportion to increase the cortisol activity, triggered by the alpha sympathetic.

The βMSH/αMSH index measures the relative level of adaptation response between the normal route (acute stress using βMSH) and the short cut using αMSH, hence the use of the adaptogen index in the formula.

The formula of this index (thyroidian index//adaptogen index) is a way to assess the relative strength of the beta sympathetic versus the alpha sympathetic:

-   -   1. The thyreotropic axis of the endocrine system is stimulated         by the beta sympathetic, hence the βMSH/αMSH index varies like         the metabolic activity of the thyroid (thyroid metabolic index).     -   2. βMSH/αMSH index increases in regular stress (with an increase         of aldosterone and decrease of potassium, i.e., a decrease in         the adaptogen index), while it decreases in the adaption short         cut, as indicated above (with an increase of potassium and         decrease of calcium, i.e., an increase of the adaptogen index),         hence the βMSH/αMSH index varies like the reverse of the         adaptogen index.

11. The metabolic estrogens index measures the metabolic activity of estrogens, and is defined as follows: Metabolic Estrogens Index=TSH/Osteocalcin.

TSH stimulates estrogens metabolic activity, and hence, the metabolic estrogens index varies like TSH.

Osteocalcin participates in the osseous anabolism under the stimulation of estrogens. The measured osteocalcin is a blood content, and therefore, the lower the osteocalcin in blood, the higher its participation in the osseous anabolism, and vice versa, hence the metabolic estrogens index varies like the reverse of osteocalcin.

By extension, the ratio TSH//osteocalcin measures the metabolic activity of estrogen.

** Publications:

a. TSH—Estrogens:

A. De Lean et al., Sensitizing Effect of Treatment with Estrogens on TSH Response to TRH, Medical Research Group in Molecular Endocrinology, Laval University Hospital Center, Quebec, Canada, AJP: Endocrinology and Metabolism, vol. 233, Issue 3, E235-E239, 1977.

I. M. Spitz et al., The Thyrotropin (TSH) Profile in Isolated Gonadotropin Deficiency: A Model to Evaluate the Effect of Sex Steroids on TSH Secretion, Population Council, New York, N.Y., USA, Dept of Endocrinology & Metabolism, Shaare Zedek Medical Center and Hebrew University, Hadassah Medical School, Jerusalem, Israel, Journal of Clinical endocrinology & Metabolism, vol. 57, N^(o) 2, 415-420.

E. Marquese et al., The effect of Droloxifene and Estrogen on Thyroid Function in Postmenopausal Women, Department of Medicine, Brigham and Women's Hospital, Harvard Institute of Medicine, Boston, Mass., USA, Journal of Clinical endocrinology & Metabolism, vol. 85, N^(o) 11 4407-4410.

D. D. Abech et al., Effects of Estrogen Replacement Therapy on Pituitary Size, Prolactin and TSH concentrations in Menopausal Women, Faculdad de Medicina, Universidad de Culaba and Porto Alegre, Brazil, Gynecology Endocrinology, vol. 4, 223-226 (2005).

b. Estrogens—Serum osteocalcin and Osteoblast proliferation:

D. C. Williams et al., Effects of Estrogen and Tamoxifen on Serum Osteocalcin Levels in Ovariectomized Rats, Bone Biology Research Group, Lilly Research Laboratories, Indianapolis, Ind. 46285, USA, Bone Miner: 1991 Sep. 14 (3) pp 205-220.

M. Nasu et al., Estrogen Modulates Osteoblast Proliferation and Function Regulated by Parathyroid Hormone in Osteoblastic SaOS-2 Cells: Role of Insulin-Like Growth Factors (IGF)-I and IGF-Binding Protein-5, Third Division, Department of Medicine, Kobe University School of Medicine, 7-5-1 Kusonoki-cho, Chuo-ku, Kobe 650, Japan, Journal of Endocrinology (2000) 167, pp 305-313.

12. The metabolic androgens index measures the metabolic activity of androgens, and is defined as follows: Metabolic Androgens Index=Metabolic Estrogens Index×Adjusted Genital Ratio, as per the above definition of the Adjusted Genital ratio, excluding the impact of adaptation. This covers the total metabolic activity of androgens at structure level, i.e., prior to the adaptation impact.

13. The growth index measures the activity of the Growth Hormone (GH) and is defined as follows: Growth index=AP Bone Isoenzymes//Osteocalcin.

Alkaline phosphatases bone isoenzymes represent the anabolism growth, as stimulated by estrogens, which target for 80% the osseous growth and for 20% the muscular growth. By extension, it may be assumed that growth-hormone GH activity varies like the bone isoenzymes.

Osteocalcin participates in the osseous anabolism, under the stimulation of estrogens. As previously noted, the measured osteocalcin is a blood content, and accordingly, the lower is the osteocalcin in blood, the higher is its participation in the osseous anabolism, and vice versa. GH activity varies like the reverse of osteocalcin

** Publications:

Anna G. Nilsson, Effects of Growth Hormone Replacement Therapy on Bone Markers and Bone Mineral Density in Growth Hormone-deficient Adults, Department of Medical Sciences, University Hospital, Uppsala, Sweden, Horm Res 2000 (54) pp 52-57.

H. Tobiume et al., Serum Bone Alkaline Phosphatase Isoenzyme Levels in Normal Children and Children with GH Deficiency: A Potential Marker for Bone Formation and Response to GH Therapy, Department of Pediatrics, Oyakama University Medical School, Okayama 700, and Diagnostic Development SRL Inc, Tokyo 163-08, Japan, The Journal of Clinical Endocrinology & Metabolism, vol. 82, N) 7 pp 2056-2061 (1997).

A. R. Baker et al., Osteoblast-Specific Expression of Growth Hormone Stimulates Bone Growth in Transgenic Mice, Department of Endocrine Research, Genentech Inc., South San Francisco, Calif. 94080, USA, Mol Cell Biol. 1992 December; 12(12) pp 5541-5547.

14. The bone remodeling index measures the level of bone remodeling and the degree of alteration of bone and bone cartilage, and it is defined as follows: Bone Remodeling Index=TSH×Growth Index.

Bone remodeling varies like the growth index as the growth index expresses the metabolic activity of the growth hormone.

Similarly, bone remodeling varies like TSH as the TSH stimulates estrogens in their contribution of growth activity, primarily towards osseous growth.

** Publications:

C. Ohisson et al., Growth Hormone and Bone, Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, Göteborg, Sweden, Endocrine Reviews 1998 Feb. 1, vol. 19(1), pp. 55-79.

K. Brixen et al., Growth Hormone (GH) and Adult Bone Remodeling: The Potential use of GH in Treatment of Osteroporosis, Department of Endocrinology and Metabolism, Aarhus University Hospital, Denmark, J Pediatry Endocrinology 1993 January-March; 6(1) pp 65-71.

15. The thyroid metabolic index measures the level of metabolic activity of the thyroid gland in its ability to provide the organism with the required energetic elements, and this index is defined as follows: Thyroid Metabolic Index=LDH/CPK.

LDH (Lactate dehydrogenase) and CPK (Creatine phosphokinase) are two enzymes that block insulin access to cells by increasing insulin resistance. Both enzymes reside in muscles and hence reduce their blood content, but they react differently:

a. CPK is typically more impacted than LDH in reaction to an increase of metabolic activity because it is immediately mobilized, and hence, its blood content will be reduced.

b. On the other hand, LDH is typically slower to move and may require an extended adaptation effort to reduce its blood content.

This differentiation in the impact of the thyroid hormones on both enzymes gives an opportunity to quantify the extent of thyroid metabolic activity by the ratio LDH//CPK: the higher the thyroid activity, the lower the CPK blood content and the higher the thyroid metabolic index.

**Publication:

Alice Muller et al., Effects of Thyroid Hormone on Growth and Differentiation of L6 Muscle Cells, Laboratory for physiology, Institute for cardiovascular research, Free University Amsterdam, The Netherlands. BAM 3 (1): 59-68, 1993.

16. The thyroid yield measures the ratio of the thyroid metabolic activity versus the pituitary level of solicitation (TSH), and it is defined as follows: Thyroid Yield=Thyroid Metabolic Index/TSH. By definition, the ratio of the thyroid metabolic index to TSH expresses the yield of the thyroid in terms of metabolic activity. A low TSH may be associated with a strong thyroid yield, and conversely, a high TSH may be associated with a low thyroid yield.

17. The parathormone (PTH) index measures the level of activity of the parathormone, a hormone produced by the parathyroid glands and secreted when the blood content of calcium is abnormally low. The parathormone primarily serves two tasks:

a. At bone level, it mobilizes the bone calcium by favoring osteolysis of the bone tissue to liberate calcium and phosphatases and increasing osteocalcin blood content.

b. At kidney level, it favors phosphatases elimination by the kidney. The PTH index is defined as: PTH Index=Ca×Osteocalcin/Thyroid Yield Index.

The PTH index varies like Ca (calcium) and Osteocalcin since their blood content increases with parathormone.

The thyroid has an osteolytic effect similar to the parathormone: if the thyroid yield is high, the parathormone does not need to act and conversely. PTH will vary like the reverse of the Thyroid yield.

18. The osteoclasic index measures the relative part of the osteoclasic activity of the thyroid, and it is defined as: Osteoclasic Index=LDH/AP Bone Isoenzymes.

The osteoclasic activity is a catabolic activity (bone destruction).

The index expresses the ratio of LDH, a catabolic action, over the alkaline phosphatases bone isoenzymes, an anabolic indication, of the bone remodeling activity. Thus, the lower the AP bone isoenzymes, the higher the osteoclasic activity.

The osteoclasic index varies like LDH and like the reverse of the AP bone Isoenzymes.

** Publications:

C. Gudmundson et al., Isoenzymes of Lactic Dehydrogenase and Esterases in Regenerating Bone, Department of Orthopaedic Surgey, Malmö General Hospital, University of Lund, Malmö, Sweden, Acta Orthopaedica, 1971, vol. 42, No 4, pp 297-304.

C. Gudmundson et al., Enzyme Studies of Fractures with Normal and Delayed Union, Department of Orthopaedic Surgery, Malmö General Hospital, University of Lund, Malmö, Sweden, Acta Orthopaedica, 1971, vol. 42, No. 1, pp 18-27.

Arthur R. Henderson, M. B., Ph.D. et al., Increased Synthesis of Lactate Dehydrogenase “H” Subunit by a Malignant Tumor, Clin. Chem. 20/11 (1974), pp 1466-1469.

19. The osteoblastic index measures the relative part of the osteoblastic activity of the thyroid, and it is defined as: Osteoblastic Index=CPK/Osteocalcin.

The osteoblastic activity is an anabolic activity (bone remodeling).

This index expresses the ratio of CPK, an anabolic activity (stimulates the creation of adenosine triphosphate ATP, a source of immediate energy for muscles) over osteocalcin blood content, which will reduce when the osteoblastic activity is high, and vice versa.

The osteoblastic index varies like CPK and like the reverse of Octeocalcin.

** Publications:

B. Fournier et al., Stimulation of Creatine Kinase Specific Activity in Human Osteoblast and Endometrial Cells by Estrogens and Anti-Estrogens and its Modulation by Calciotropic Hormones, Ciba-Geijy Ltd, Basel, Switzerland, Journal of Endocrinology, 1996, August; 150(2), pp 275-285.

T. Yoshikawa et al., In Vitro Bone Formation Induced by Immunosuppressive Agent Tacrolimus Hydrate (FK506), Department of Orthopedic Surgery, Nara Medical University, Kashihara, Japan, Tissue Eng. March/April 2005, 11(3-4), pp 609-617.

20. The turnover index measures the length of the cell renewal cycle in terms of the time it takes to get a cell renewal. The higher the turnover index, the slower the renewal, and the lower the turnover index, the faster the renewal.

The turnover index is defined as: Turnover Index=TSH×AP Bone Isoenzymes.

TSH indirectly expresses the catabolic activity, necessary for any cell renewal activity. The lower the TSH, the stronger the thyroid, the faster the renewal and the lower the turnover index, hence the turnover varies like TSH.

Relative to the Alkaline phosphatases bone isoenzymes, cell renewal is a catabolic activity and the slower the renewal, the higher the turnover, the higher the anabolism, hence the turnover index varies like the alkaline phosphatases bone isoenzymes, which represents the anabolic activity, particularly in the osseous area (alkaline phosphatases bone isoenzymes hydrolyse organic phosphatases to produce indissoluble mineral phosphatases, hence their notable role in the calcification, at joints level, and in the mineralization of the skeleton).

In summary the Turnover varies like the product TSH×AP Bone Isoenzymes.

21. The intra-cellular growth index measures the level of intra-cellular activity of growth factors, and is defined as follows: Intra-cellular Growth Index=Growth Index/Turnover Index.

The intra-cellular growth index varies like the growth index, adjusted by the speed of cell renewal (turnover index). Thus, when turnover is low (hence fast renewal), the intra-cellular growth activity is high; and conversely, when the turnover is high (hence slow renewal), the intra-cellular growth activity is low.

22. The anti-growth index measures the level of activity of the anti-growth factors, and is defined as: Anti-growth Index=1/Intra-cellular Growth Index. As reflected in the formula, the anti-growth index varies like the reverse of the intra-cellular growth index. That is, the higher the intra-cellular growth index, the lower the anti-growth activity (and anti-growth index), and vice versa.

23. The somatostatin index measures the level of activity of the somatostatin and provides a way to assess the overall activity of the exocrine pancreas. The somatostatin index is defined as: Somatostatin Index=Anti-growth Index/Cortisol Index.

The somatostatin hormone is a strong inhibitor of the growth hormone, as per the research studies referred below. It is one of the main anti-growth factors and it varies like the anti-growth index.

Cortisol increases growth hormone receptors activity, as per research studies referred below, while somatostatin has a reverse effect on the same receptors, and consequently, the somatostatin index varies like the reverse of the cortisol index.

** Publications:

F. R. Ward et al., The Inhibitory Effect of Somatostatin on Growth Hormone, Insulin, and Glucagon secretion in Diabetes Mellitus, Depts of Reproductive Medicine and Medicine, School of Medicine, University of California, San Diego, La Jolla, Calif., USA, Journal of Clinical Endocrinology & Metabolism (1975), vol. 41, N^(o) 3, pp 527-532.

P. Brazeau et al., Inhibition of GH Secretion in the Rat by Synthetic Somatostatin, The Salk Institute fot Biological Studies, La Jolla, Calif., U.S.A., Journal of Endocrinology (1974), vol. 94, N^(o) 1, pp 184-187.

D. Swolin-Eide et al., Cortisol Increases Growth Hormone Receptor Expression in Human Osteoblast-Like Cells, Research Center for Endocrinology and Metabolism, Dept of Internal Medicine, and Dept of Hand Surgery, Sahlgrenska University Hospital, Goteborg, Sweden, Journal of Endocrinology (1998), vol. 156, Issue 1, pp 99-105.

A. Schonbrunn, Glucocorticoids Down-Regulate Somatostatin receptors on Pituitary cells in Culture, Department of Physiology, Harward school of Public Health, Boston, Mass., USA, Journal of Endocrinology (1982), vol. 110, N^(o) 4, pp 1147-1154.

A. P. Silva et al., Regulation of CRH-Induced Secretion of ACTH and Corticosterone by SOM230 (Somatostatin Analogue) in Rats, Novartis Institute for BioMedical Research, Basel, Switzerland, European Journal of Endocrinology (2005), vol. 153, Issue 3, pp 7-10.

24. The prolactin index measures the functional activity of the prolactin. This hormone plays a notable role in the reactivation of the adaptation process, influencing catabolism and anabolism, growth and anti-growth factors, at cell and tissular levels.

The prolactin index is defined as: Prolactin Index=Somatostatin Index×TSH/Growth Index.

The prolactin index varies like the somatostatin index in that prolactin is part of the somatotropic axis and plays a role in balancing growth and anti-growth. It inhibits Growth hormone, hence it varies like the reverse of Growth index.

Prolactin is stimulated by TRH, hence it varies like TSH, also stimulated by TRH.

25. The insulin index measures the functional activity of insulin and is defined as: Insulin Index=100×Cata-Ana Index/TSH×Turnover Index.

The insulin, in its role of bringing immediate energy through the initial adaptation syndrom, varies like the Cata-Ana index, which represents the mobilization of factors participating in the set up of the immediate defense system.

Insulin acts also along the thyroid in its role of mobilizing energetic reserves, and hence, it varies like the reverse of TSH (a strong TSH, hence a weak thyroid, inhibits insulin; and conversely, a weak TSH, hence a strong thyroid, increases insulin).

A third role of insulin is to increase cell nutrition to support cell renewal and growth, and hence, it varies like the reverse of the turnover index: a low turnover is a sign of fast cell renewal hence an increase of cell nutrition and an increase of insulin, conversely, an increase of turnover decreases insulin activity.

The factor 100 has been added to maintain the index in a bandwith similar to other related indexes.

Consequently, the insulin index varies like the Cata-Ana index and like the reverse of TSH and Turnover, with an adjustment factor of 100.

** Publications:

V. Lafargia et al., The Effects of Insulin on TSH Secretion and the Morphology and Physiology of the Thyroid in the Lizard Podarcis Sicula, Department of Comparative Biology, Universita degli Studi di Napoli, Naples, Italy, Amphibia-Reptillia (1996), vol. 17, no. 1, pp. 39-45.

R. P. Lamberton et al., Insulin Hypoglycemia Suppresses TSH Secretion in Man, Tufts New England Medical Center Hospital, Boston, Mass., USA, Hormone and Metabolic Research, vol. 18, no. 1, pp. 76-77 (1986).

26. The insulin resistance index measures the inhibition level of the insulin activity at the membrane level, independent of its temporary activity linked with the general adaptation syndrome. It is defined as: Insulin Resistance Index=Somatostatin Index/Insulin Index.

As insulin resistance is a growth hormone inhibitor at the cell level, the insulin resistance index varies like somatostatin.

Conversely, the Insulin resistance index varies like the reverse of insulin, outside of adaptation (the insulin resistance index decreases when insulin is high in order to facilitate the glucose access to cells, and it increases when insulin is low).

In instances of stress, Insulin resistance may selectively prevent glucose access to cells in non-priority organs in order to secure the energy distribution to priority organs (heart, brain, muscles).

27. The demyelination index measures the adaptative activity of insulin in its timing relationship to the adaptative activity of the growth hormone, and it is defined as: Demyelination Index=Insulin Index/(Growth Index×Intra-cell Growth Index).

The demyelination index expresses the chronology insulin-growth factors, i.e., the demyelination increases when insulin anticipates on growth factors, under the influence of glucagon.

Also present in the demyelination index, the growth index and the intra-cell growth index: both express the same thing in terms of growth hormone activity or in terms of cell growth. They amplify the demyelination risk (the lower the growth hormone or the intra-cell growth, relative to insulin, the higher the demyelination risk).

28. The next number of example indexes describes the cell activity between the nucleus and the membrane, as well as the various types of cellular death. These indexes include a nuclear/membrane index, membrane expansion rate, structural expansion rate, membrane fracture rate, apoptosis rate, necrosis rate and fibrosis rate.

28-1. The nuclear/membrane index measures the level of metabolic activity of the nucleus relative to the membrane activity, and is defined as: Nuclear/Membrane Index=Metabolic Estrogens Index/Growth Index.

The focus target of estrogens metabolic activity is the nucleus, while the focus target of the growth hormone metabolic activity is the membrane.

By definition the nuclear/membrane index is the ratio of the estrogens metabolic activity index over the growth hormone activity index, which has a respective impact on cell Nucleus and membrane.

28-2. The membrane expansion rate measures the metabolic activity of the membrane, and is defined as: Membrane Expansion Rate=Catabolism Rate×Intra-cell Growth Index.

In this index, the catabolism rate is the starting point of any cell membrane expansion, and the intra-cell growth index represents the intra-cell activity of growth factors.

Both indexes have an amplification impact on the Membrane expansion.

A strong membrane expansion rate represents a strong dominance of growth factors over structural factors: the higher it is and the higher is the risk of membrane fracture leading to necrosis (see below).

Notably, the catabolism rate is yet another index, which is defined as the ratio of the thyroid metabolic index to the adrenal gland index (Catabolism Rate=Thyroid Metabolic Index/Adrenal Gland index).

In this regard, catabolism depends almost in large part upon the thyroid metabolic activity, and logically it varies like the thyroid metabolic index.

Also, adrenal hormones favor both anabolism through adaptation and catabolism through permissivity over the thyroid. The adrenal gland index functions as a moderating factor in the catabolism rate index since a strong glucocorticoid response usually generates an hypo-catabolism, hence the catabolism rate varies like the reverse of adrenal gland activity.

28-3. The structural expansion rate measures the metabolic activity of the nucleus. The structural expansion rate index is defined as follows: Structural Expansion Rate=Anabolism Rate Index×Nuclear/Membrane Index.

For this index, the anabolism rate, which represents the anabolism metabolic activity driven by estrogens over the nucleus, is defined by Catabolism rate/Cata-Ana Index. The nuclear/membrane index represents the level of metabolic activity of the nucleus relative to the membrane activity. And similar to the membrane expansion rate, both above indexes have an amplification impact on the structural expansion rate.

28-4. The membrane fracture rate measures the degree of fragility of the membranes and hence their risk of fracture. It is defined as: Membrane Fracture Rate=Metabolic Yield Index/(TSH×Turnover Index).

Overall metabolic activity is required to support a membrane expansion, and as such, the membrane fracture rate varies like the overall metabolic yield which is the sum of both catabolic and anabolic activities.

Membrane fracture also requires strong thyroid activity, the higher the thyroid throughput, the lower the TSH—and hence, the membrane fracture rate varies like the reverse of the TSH.

Finally, membrane fracture is the consequence of a fast cell renewal (the faster the cell renewal, the lower the turnover). And consequently the membrane fracture rate varies like the reverse of the Turnover index.

28-5. The apoptosis rate measures the level of apoptosic activity for the whole organism. It is an indication of nucleus overactivity and acceleration of cell growth process. The apoptosis rate increases when the cell growth is normal, and decreases when the cell growth is abnormal or when the organism is in a deceleration of growth. The apoptosis rate is defined as: Apoptosis Rate=Structural Expansion Rate/Membrane Expansion Rate.

The structural expansion rate represents the metabolic activity of the nucleus (the higher the structural expansion rate, the higher the likelihood the cell is in a programmed death, for a limited number of divisions. Apoptosis, which measures the cell programmed death activity, varies like the structural expansion rate.

Apoptosis varies like the reverse of the membrane expansion rate. The higher the membrane expansion rate, the lower the apoptosis and the higher the risk of membrane fracture (with cell implosion leading to necrosis instead of apoptosis), and vice versa.

28-6. The necrosis rate measures the level of cellular implosion by necrosis relative to apoptosis. It is the other type of cellular death, with waste, generally associated with local inflammation. The necrosis rate is defined as: Necrosis Rate=Membrane Fracture Rate/Apoptosis Rate. As necrosis is a consequence of membrane fracture, the necrosis rate varies like the membrane fracture rate. And as the definition of the necrosis rate is relative to apoptosis, the necrosis rate varies like the reverse of the apoptosis rate.

28-7. The fibrosis rate measures the fibrosis activity of the organism, from a simple isolation of a tissue to a degenerative sclerosis of a set of tissues or an organ. Fibrosis is part of the growth process: it participates in organ growth in order to prevent excessive growth. The fibrosis rate is defined as: Fibrosis Rate Index=(TSH)²×(Osteocalcin)³/100. In this formula, the power used for both TSH and osteocalcin differentiates the relative weight of both components in the measurement of the fibrosis activity. The 100 denominator keeps the index in a normal bandwidth relative to other indexes.

The fibrosis rate varies like the TSH. In this regard, as fibrosis is an anti-growth factor, it is typically favored by a weak thyroid, and hence, a strong TSH.

Similarly, fibrosis rate varies like the reverse of bone osteocalcin. A strong fibrosis is linked with an imbalance of the calcium metabolism associated with a decrease of the osteocalcin in the fibrosed area, hence an increase of the osteocalcin blood content. Fibrosis will vary like the osteocalcin blood content.

Having introduced a number of example indexes of the Biological Simulation Model, the following discussion presents a number of example cases in which one or more indexes have been tested in relation to one or more pathologies, some of which also illustrate the effects of classical treatments on the indexes.

4-2. Testing the Biological Simulation Model on Pathologies

As described herein, testing the Biological Simulation Model on pathologies may be sub-divided as follows:

4-2-1. Testing One Index and One Pathology:

Example Case 1: Histamine index and Eczema,

Example Case 2: Histamine index and Rhinitis,

Example Case 3: Demyelination index and Multiple Sclerosis,

Example Case 4: Insulin index and Mucoviscidosis,

Example Case 5: Insulin resistance index and Down syndrome,

Example Case 6: Bone remodeling index and Bone metastases, and

Example Case 7: Bone remodeling index and Osteoporosis.

4-2-2. Evaluation of Classical Treatments:

Example Case 8: LH RH analogues over FSH/LH and androgens,

Example Case 9: Chemotherapy over Histamine, and

Example Case 10: Cortisone on Chronic allergy (asthma).

4-2-3. Multiple Patients with One Pathology:

Example Case 11: Fibromyalgia (20 sick versus 20 healthy).

4-2-4. Major Relevant Indexes for a Given Pathology:

Example Case 12: Metastasized Colon cancer, and

Example Case 13: Metastasized Prostate cancer.

4-2-1: Testing One Index and One Pathology

In the following seven example cases, one index has been tested in relation to one pathology.

EXAMPLE CASE 1 Histamine Index and Eczema

In this first example, consider the case of a six-year-old female suffering from generalized eczema at the time of her first consultation on Apr. 30, 2003. The patient's father is cutaneous allergic, and the patient has been previously diagnosed with asthma (treated by Becotide and Ventoline) and chronic rhinopharyngitis. The patient was first diagnosed with generalized eczema at age eighteen months, and had previously been treated (without success) with local corticoids.

Following her first consultation, the patient was given a terrain treatment and experienced a complete healing in two months. Her healing was confirmed by blood analysis at a second consultation on Sep. 27, 2003, at which time her histamine index levels also dropped to within designated normal levels for a female, as reflected in the below table.

Female Norms Date Mar. 4, 1930 Mar. 9, 1927 Mini W Maxi W Histamine Index 387 55 20 60

** Publication:

J. Ring, Plasma Histamine Concentrations in Atopic Eczema, Dermatology Department, Ludwig Maximilians University Munich, West Germany, Clin Allergy, 1983 November, 13(6): pp 545-52.

EXAMPLE CASE 2 Histamine Index and Allergic Rhinitis

In a second example, consider the case of a forty-two-year-old female at the time of her first consultation in January 2003. Since puberty, the patient has suffered from a chronic rhinitis with seasonal allergic symptoms. The patient has received various treatments (corticoids, antiallergic drugs, beta-stimulants) with limited success. But chronicity has increased through time, with symptoms becoming permanent, such as full nasal obstruction, postnasal drips and very frequent sneezing.

Analysis of the patient's blood work shows a very high histamine index at 1085 versus designated norm levels for a female from 20 to 60. An appropriate treatment reduced the index by eighty-five percent over a year period: the signs of rhinopharyngitis have fully disappeared and the patient feels a complete healing. No relapse during a six-year period following the patient's first consultation. The data below illustrate the patient's histamine index at her first consultation, and at second and third subsequent consultations—the second and third consultations occurring approximately four months and one year, respectively, after the first consultation.

Female Norms Date Mar. 1, 1913 Mar. 5, 1912 Apr. 1, 1905 Mini W Maxi W Histamine Index 1085 889 157 20 60

** Publication:

A. Weyer et al., Seasonal Increase of Spontaneous Histamine Release in Washed Leucocytes from Rhinitis Patients Sensitive to Grass Pollen, Unité d'Immuno-Allergie, Institut Pasteur, Paris, France, Clin Exp Immunol, 1990 March, 79(3): 385-391.

EXAMPLE CASE 3 Demyelination Index and Multiple Sclerosis

In a third example, consider the case of a twenty-eight-year-old male who since 1993 has suffered from chronic sensitivity disorders at the level of limbs and thorax, a type of multiple sclerosis (MS). The patient has experienced chronic relapses of symptoms requiring corticoid treatment over short period of time. In July 1995, the patient suffered retrobulbar optic nevritis on his left eye, which was treated by high-dose corticosteroid embolization. And beginning in 1998, the patient has been treated with Interferon Beta since 1998, one injection per week.

As can be seen in the graph of FIG. 1, the demyelination index for this patient is strictly correlated with the time of activation of the pathology, i.e., August 1999, August 2001, November 2003, October 2005, January 2007 and June 2008.

** Publication:

Cortical Demyelination and Diffuse White Matter Injury In Multiple Sclerosis,

Kutzelnigg A, Lucchinetti C F, Stadelmann C, Brück W, Rauschka H, Bergmann M, Schmidbauer M, Parisi J E, Lassmann H.,

Center for Brain Research, Medical University of Vienna, Vienna, Austria,

Brain, 2005 November; 128(Pt 11): 2705-12. Epub 2005 Oct. 17.

EXAMPLE CASE 4 Insulin Index and Mucoviscidosis (Cystic Fibrosis)

In a fourth example, consider the cases of two patients previously diagnosed with cystic fibrosis, and a third patient experiencing similar insulin index levels.

The first case is of a five-year-old male diagnosed with cystic fibrosis at the age of two. As shown in the table below, the trend of the insulin index over a five and one-half year period shows a stable picture at a very low level. More particularly, the trend shows that the insulin index averages 10% of the designated normal levels (1.5 to 5.0), with nearly identical levels at beginning of the period (0.15 in November 2003) and end of the period (0.12 in May 2009).

(Mini/Maxi Norms: 1.5 to 5.0) Case 1 November November October May May May 2003 2004 2005 2006 2007 2009 Insulin index 0.15 0.08 0.25 0.32 0.12 0.12

The second case is of a four-and-one-half-year-old female diagnosed with cystic fibrosis at the age of one. As shown in the table below, the insulin index is below the designated normal levels (1.5 to 6.0) at the time of her first consultation and tends to decrease gradually through time over a four-year period.

(Mini/Maxi Norms: 1.5 to 5.0) Case 2 July July June May June November 2005 2006 2007 2008 2009 2009 Insulin index 1.05 0.34 0.28 0.20 0.45 0.30

And the third case is of a seventeen-year-old female not previously diagnosed with cystic fibrosis. As shown in the table below, the insulin index for this patient is also significantly below the designated normal levels (1.5 to 6.0), confirming the two previous cases of cystic fibrosis with low insulinic activity, and being confirmed by Research studies, as stated below

Male/Female Norms Date January 1999 Mini Maxi Insulin index 0.45 1.5 5

** Publication:

E. M. Laursen et al., Diminished Concentrations of Insulin-Like Growth Factor I in Cystic Fibrosis, Dept of Growth and Reproduction GR, State University Hospital, Copenhagen, Denmark, Arch Dis Child 1995; 72:494-497 doi:10.1136/adc.72.6.494.

EXAMPLE CASE 5 Insulinic Resistance and Down Syndrome

In a fifth example, consider the case of a male with Down syndrome. As shown in the table below, the patient has an insulin resistance index that consistently trends at very high levels relative to the designated normal levels, at least in the in the early phase of childhood, confirmed by Research studies as stated below.

Date January May January September 2007 2008 2009 2009 Male Norms Age (years) 2 3 5/12 4 ¼ 4 ⅚ Min Max Insulin 13212 307 1163 1050 0.75 1.25 Resistance

** Publications:

E. J., Hoorn et al., Insulin Resistance in an 18-Year-Old Patient with Down Syndrome Presenting with Hyperglycaemic Coma, Hypernatraemia and Rhabdomyolysis (Case Report), Erasmus Medical Center, Rotterdam, The Netherlands, Journal of internal medicine, 2005, vol. 258, n^(o) 3, pp. 285-288 [4 page(s) (article)] (19 ref.).

C. T. Fonseca et al., Insulin Resistance in Adolescents with Down Syndrome: A Cross Sectional Study, Medicina School, HUCFF, Federal University of Rio de Janeiro, Brazil, Genetics dept, IPPMG, Ilha de Fundao, Rio de Janeiro, Brazil, Pediatrics Dept, HUCGG, Ilha de Fundao, Rio de Janeiro, Brazil, Endocrinology Dept, HUCFF, Ilha de Fundao, Tio de Janeiro, Brazil, BMC Endocrine Disorders 2005, vol. 5 PubMed doi:10.1186/1472-6823-5-6.

EXAMPLE CASE 6 Bone Remodeling and Osseous Metastases

In a sixth example, consider the cases of two patients. The first patient was, at the time of his first consultation in July 2000, a fifty-nine-year-old male diagnosed seven years prior with prostate cancer undergoing hormonotherapy treatment. In July 2000, the patient was suffering from paraplegia of the lower extremities, with destruction of D9 vertebra and compressive external pachymeningitis. Generalized osseous metastases is discovered and treated with radiotherapy. The patient died in November 2000, approximately four months following his first consultation.

As shown in the table below, the patient's bone remodeling index surged from the patient's first consultation through two subsequent consultations, thereby giving an indication of the speed of the cancer osseous expansion.

Male Norms Date July 2000 August 2000 October 2000 Mini Maxi Bone Remodel Index 43 33 115 2.5 8.5

At the time of his first consultation in January 2007, the second patient was a sixty-four-year-old male. Eight years earlier, in October 1998, a PSA control yielded a level of 85 ng/ml (norm<5.0), indicating a poorly-differentiated prostate adenocarcinoma, with extension to the right seminal vesicle. The patient was treated with radiotherapy of forty-five grays over the prostate and twenty-five grays over the pelvis area. In December 1998, a lymphadecnotomy revealed a contaminated ilio-obturator lymph node, for which the patient was treated with a single injection of LH RH analogue for three months, and then Casodex (three capsules per day) for several years. Then, in July 2006, the patient's PSA level showed a gradual increase, leading to additional radiotherapy on the pelvic area (eight sessions).

At the time of the second patient's first consultation in January 2007, the patent was suffering from multiple metastases concerning ureters with bilateral pulmonary metastases. Approximately eleven months thereafter, in December 2007, the patient died following a renal blocking secondary to the bilateral ureteral metastatic obstruction. The table below shows the bone remodeling index for the second patient for a portion of the final year of the patient's life. As shown, the bone remodeling index trend shows some temporary improvement during 2007, until the organism started escaping from the treatment in October 2007.

(Male Norms: 2.5 to 8.5) Date January March May August September December 2007 2007 2007 2007 2007 2007 Bone 62 36 25 16 17 80 Remodel Index

EXAMPLE CASE 7 Bone Remodeling and Osteoporosis

In a seventh example, consider the case of a fifty-five-year-old female at the time of her first consultation in May 2009. For approximately four years prior, beginning in 2005, the patient had undergone hormone replacement therapy for menopause, and undergone Utrogestan, Estrogel, vitamin D and calcium treatment for spinal osteoporosis, although her initial bone remodeling was normal. In August 2009, the patient suffered a crush fracture of her T6 vertebra with low bone mineral density diffused through the entire vertebral body.

As shown in the graph of FIG. 2, for a period of approximately four months before the patient suffered the crush fracture, the patient's bone remodeling index decreased from an already low level of 0.72 in January 2009 to 0.29 in May 2009 (from norm levels between 2.5 and 8.5)—explaining the crush fracture that the patient would suffer approximately three months later.

The table below illustrates the results of an osteodensitometry procedure performed on the patient approximately four months after she suffered the crush fracture. The procedure confirmed the magnitude of bone loss. The patient's Bone Mineral Density (BMD) tested at 0.651 g/cm2, which is 25% lower than the average woman of the patient's same age (−2.0 Standard Deviations SD).

Osteodensitometry cv BMD T Score Z Score Percentile (Dec. 4, 2009) (%) (g/cm2) (SD) (SD) (%) Thigh Bone total zone 0.8 0.874 −1.3 −0.5 31 cervical zone 1.7 0.66 −1.9 −0.6 27 ward zone 2.6 0.515 −2.3 −0.5 31 Forearm ultra distal zone 1 0.36 −0.5 0 50 proximal zone 1.5 0.658 0.2 0.9 82 Front rachis exam 0.9 0.651 −3.4 −2 2 BMD observed 0.651

** Publications:

Bone Remodeling in Osteoporosis,

M. C. de Vernejoul,

INSERM U18, Hôpital Lariboisière, 6 rue Guy Patin, 75010 Paris, France,

Clinical Rheumatology, vol. 8, Supplement 2/June 1989.

Bone Marrow, Cytokines, and Bone Remodeling—Emerging Insights into The Pathophysiology Of Osteoporosis,

S C Manolagas, M.D., Ph.D., and R L Jilka, Ph.D., Dept of Internal Medicine, University of Arkansa for Ledical Sciences, Little Rock, USA, The new England Journal of Medicine, vol. 332:305-311, N^(o) 5, Feb. 2, 1995.

4-2-2: Evaluation of Classical Treatments

The following next three example cases illustrate the effects of classical treatments on the indexes.

EXAMPLE CASE 8 Effects of LH RH Analogs (Decapeptyl/Triptorelin/Leuprolide) Treatment over FSH, LH and Androgens

In this eighth example, consider the case of a sixty-two-year-old male at the time of his first consultation in December 2008. In April 2004, the patient underwent a radical prostatectomy with lymph nodes dissection. The patient had also twice undergone chemotherapy treatment, first using Taxotere® for a three-month period from August to November 2006, and then using Zometa® for a three month period from May to August 2007. In December 2007, approximately a year before his first consultation, the patient was also diagnosed with multiple osseous metastases, which had been treated with Sutent® (37.5 mg/day).

The graphs of FIGS. 3, 4 and 5 show the blocking effects of an injection of Decapeptyl (Triptorelin) given June 1, 2009 (about six months after the patient's first consultation), over FSH, LH, tissular androgenic and DHEA activities.

FIG. 3 illustrates FSH and LH indexes (norms 0.3 to 8.0). Both curves show the effect of the Triptoreline injection on June 1st reducing by a factor E7 between March and August, with a rebound in November, when the injection is 6 months old.

FIG. 4 illustrates tissular androgen activity (norms 0.09 to 0.13), and shows a similar kind of drop from 1.08 to 0.01 between March and August, with a rebound in November when the injection is 6 months old.

FIG. 5 illustrates the DHEA activity index (norms 2 to 6), and shows a similar kind of drop from 2.0 to 6.5 E -7 between March and August, with a rebound in November, when the injection is 6 months old.

** Publications:

Comparative Efficacy of Triptorelin Pamoate and Leuprolide Acetate in Men with Advanced Prostate Cancer,

South African Triptorelin Study Group: C F Heyns, M L Samonin, P Grosgurin,

R Schall. C H Porchet,

Dept of Urology University of Stellenbosch, Tygerberg Hospital, Western Cape, South Africa,

Debiopharm S A, Lausanne, Switzerland,

Quintiles ClinData, Bloemfontein, South Africa,

BJU international, 2003, vol. 92, n^(o) 3, pp. 226-231.

Leuprolide Acetate: A Drug of Diverse Clinical Applications,

A C Wilson, S Vadakkadath Meethal, R Bowen, C S Atwood,

Dept of Medicine and Geriatric Research, University of Wisconsin, Madison Wis., USA,

Dept of Pathology and Laboratory Medicine, Madison Wis., USA,

ORB Research, Charleston S.C., USA,

Case Western University, Cleveland Ohio, USA,

Expert Opinion on Investigational Drugs, vol. 16, no. 11, November 2007, pp. 1851-1863(13).

Comparative Efficacy of Triptorelin Pamoate and Leuprolide Acetate in Men with Advanced Prostate Cancer,

South African Triptorelin Study Group: C F Heyns, M L Samonin, P Grosgurin, R Schall. C H Porchet,

Dept of Urology University of Stellenbosch, Tygerberg Hospital, Western Cape, South Africa,

Debiopharm S A, Lausanne, Switzerland,

Quintiles ClinData, Bloemfontein, South Africa,

BJU international, 2003, vol. 92, n^(o) 3, pp. 226-231.

Leuprolide Acetate: A Drug of Diverse Clinical Applications,

A C Wilson, S Vadakkadath Meethal, R Bowen, C S Atwood,

Dept of Medicine and Geriatric Research, University of Wisconsin, Madison Wis., USA,

Dept of Pathology and Laboratory Medicine, Madison Wis., USA,

ORB Research, Charleston S.C., USA,

Case Western University, Cleveland Ohio, USA,

Expert Opinion on Investigational Drugs, vol. 16, no. 11, November 2007, pp. 1851-1863(13).

EXAMPLE CASE 9 Chemotherapy and Histamine Induction in a Cancer Patient

In a ninth example, consider the case of a female who in June 2002, at the age of forty seven, underwent a full right breast mastectomy, with auxilary curage of four metastatic lymph nodes with capsule tear, among six identified lymph nodes (4N+/4R+/6). As to the patient's histology: she had an infiltrating ductal carcinoma SBR (Scarff-Bloom-Richardson) grade I, 4 cm long, concerning the area behind the nipple and external quadrants, and infiltrating the nipple, with colonization of the epidermis on surface. The patient also had a noticeable a small infiltrating carcinoma 8 mm long at a distance of the external quadrants junction. The limits of ablation were healthy tissue.

An immunohistochemical analysis showed that the infiltrating carcinoma was Estrogen Receptor negative and slightly Progesterone Receptor positive.

In addition, between August and November 2002, the patient underwent adjuvant chemotherapy treatment made of six cycles, based on Adriamycin (86.5 mg), Ifosfamide (1165 mg) and Taxotere® (130 mg) within a BCIRG005 protocol. The patient did not take any other medication or undergo any other treatment, including cortisone, antiemetic or stimulating of bone marrow.

FIG. 6 illustrates the patient's histamine index over a period of time, with the arrows indicating the dates of the patient's chemo sessions. As shown, the dates of the chemo sessions are indicated by arrows on the graph (Aug. 8, Aug. 29, Sept. 19, Oct. 10, Oct. 31, Nov. 21, all 2002).

The illustrated histamine index trend shows a peak after perfusion and a subsequent return to the basal state, which is getting more and more difficult through time, until the chemotherapy ends. This may open new opportunities for tracking patients under chemotherapy treatment. In this regard, the time to get to the peak of the histamine reaction and its intensity may permit one to identify a patient's risks to strong histaminic reactions with their associated effects (e.g., nauseas, vomiting, cephalgias, various allergies, etc.) and, if desired, apply a corrective complementary therapy.

Publication:

Effect of Paclitaxel (Taxol) and Its Solvent Cremophor EL on Mast Cell Histamine Secretion and Their Interaction with Adriamycin,

G Decorti, B F Klugman, L Candussio, L Baldini,

Department of Biomedical Sciences, Faculty of Medicine, Trieste, Italy,

Anticancer Res 1996 January-February, vol. 16, N^(o) 1, pp 317-320.

EXAMPLE CASE 10 Effect of Cortisone on Chronic Allergy (Asthma)

In a tenth example, consider the case of a sixty-two-year-old female with osteoporosis and multiple food intolerances, and who has suffered from asthma since childhood. The patient is given cortisone (60 mg/day) for two months prior to a consultation on Apr. 19, 2010. The patient's related index evolution between Jan. 26, 2010 and Apr. 19, 2010, and the consultation looks as follows:

Female Norms Index Oct. 1, 1926 Oct. 4, 1919 Mini Maxi Cortisol 0.4 14.5 3 7 ACTH 676004 0.25 0.7 3 DHEA 251080 4 5 9 Adaptation Ratio 3.30 0.16 0.25 0.5 (Eosinophils) 22.1 1.3 1 5 Histamine 11969 15 20 60 Bone Remodeling 8 27 2.5 8.5 Parathormone 16.9 3.1 2 42

As shown in the above table, as a consequence of the cortisone treatment, the cortisol jumps by a very large factor (over 30). Example embodiments of the present invention can detect a high level of cortisol without measuring it in the blood. Relative to the ACTH index, physiological studies (as referred below) have demonstrated that an upsurge in cortisol blocks the ACTH, which maybe identified by example embodiments without measuring it in blood. As also shown, DHEA being under control of ACTH, the DHEA index sharply declines, together with ACTH, as indicated by its measurement. Further, the increase in cortisol results in a significant reduction in the eosinophils, and consequently a decrease in the histamine index. And a large increase in cortisol, through its catabolic effect on bone, may increase the bone remodeling index, coupled with a significant decrease of parathormone, in reaction to the liberation of calcium by the bone catabolism. The related indexes show a large consistency with the physiological moves identified in Research papers listed below.

** Publications:

Alterations in Cortisol Negative Feedback Inhibition as Examined Using the ACTH Response to Cortisol Administration in PTSD,

R Yehuda, R K Yang, M S Buchsbaum, J A Goller,

The Traumatic Stress Studies Program, Psychiatry Department, Mount Sinai School of Medicine, and the Bronx Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, N.Y. 10468, USA,

Psychoneuroendocrinology (2006) May; 31(4): pp 447-451.

Effect of ACTH and Prolactin on Dehydroepiandrosterone (DHEA), Its Sulfate Ester and Cortisol Production by Normal and Tumorous Human Adrenocortical Cells,

T Feher, K S Szalay, and G Szilagyi,

Hungarian Academy of Sciences, Postgraduate Medical School and Semmelweis University Medical School, Budapest, Hungary,

Journal Steroid Biochemistry (1985) August; 23(2): pp 153-157.

Eosinophils Activate Mast Cells to release Histamine,

A M Piliponsky, D Pickholtz, G J Gleich, F Levi-Schaeffer,

Dept of Pharmacology, School of Pharmacy, The Hebrew University-Hassad Medical School, Jerusalem, Israel,

Dept of Immunology, Mayo Clinic and Foundation, Tochester, Minn., USA,

Int. Arch Allergy Immunology (1999) 118, N) 2-4, pp 202-203.

Profiles of Endogenous Circulating Cortisol and Bone Mineral in Healthy Elderly Men,

E. Dennison, P. Hindmarsh, C. Fall, S Kellingway, D Barker, D Philips and C Cooper,

Medical Research Council Environmental Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK,

Cobbold Laboratories, Middlesex Hospital, London, UK,

The Journal of Clinical Endocrinology & Metabolism (1999),

Journal of Endocrinology (2009) 201, pp 241-252Vol 84, N^(o) 9, pp. 3058-3063.

Cortisol Mobilizes Mineral Stores from Vertebral Skeleton In The European Eel: an Ancestral Origin for Glucocorticoid-Induced Osteoporosis,

M Sbaihi, K Rousseau, S Baloche, F Meunier, M Fouchereau-Peron, and S Dufour,

Museum Natioal d'Histoire Naturelle, Paris, France,

Marine Station of Concarneau, Concarneau, France.

4-2-3: Multiple Patients with One Pathology

EXAMPLE CASE 11 Study of Fibromyalgia Cases Versus Healthy Cases (2×20)

In the following eleventh example case, multiple patients with one pathology are evaluated. In this example, consider a sampling of twenty females aged between 30 and sixty (with one-third from 40 to 50) who suffer from fibromyalgia, and a similar sampling of twenty healthy females. In the patients with fibromyalgia, the most commonly-observed symptoms include: muscular pains and inflammatory lesions, abdominal pains, insomnia, headaches, anxiety and depression, gastro-oesophageal reflux disease (GERD) and chronic fatigue.

The Biological Simulation Model of example embodiments of the present invention identified in the patients with fibromyalgia a number of areas of endocrine imbalance, as illustrated in the below table. For example, these patients had an excess of aldosterone that may create swellings and peripheral edemas, and an excess of peripheric serotonin (shortage of central serotonin) that may create depression, migraines, headaches headaches and gastro-intestinal troubles (GERD). These patients also exhibited the following: a shortage of somatostatin (hypo function of exocrine pancreas), an excess of insulin, relative to insulinic resistance, an excess of intra-cell insulinic activity: high cell permeability and osmolarity, and an excess of oxidoreduction and free radicals.

Median Values Female Norms Index Healthy Fibromyalgia Mini Maxi Aldosterone 756 10818 77 2688 Peripheral Serotonin 5.1 26.2 1.5 7.5 Somatostatin 1.9 0.5 1.5 5.0 Insulin versus Insulin resistance 2.9 43.8 2 4 Intra-cell insulinic activity 4.6 47.9 8 12 (cell osmolarity) Oxidoreduction 0.4 2934 0.7 2.0 Free Radicals excess 10 4848 2 6

This eleventh example illustrates the multiplicity of the dysfunctions underlying the broad scope of the fibromyalgia syndrome observed in a group of patients. For a given patient, the distribution of the relevant indexes, coupled with the clinical examination, may permit one to develop the appropriate therapeutic. For example, a patient may be treated to reduce aldosterone if the patient is suffering from swellings and peripheral edemas, and/or treated with supporting central serotonin if the patient is suffering from neurologic troubles (depression, headaches, etc.). The majority of patients suffer from metabolic troubles associated with a cell overnutrition affecting the muscles, associated with a hypofunctioning of the exocrine pancreas (low somatostatin), and coupled with an excess of oxidation and free radicals. For fibromyalgia, as for kinds of syndromes, example embodiments of the present invention permit an extended study of the pathology, which affects a large part of the population, by working on much larger samples in order to break the broadly called “fibromyalgia syndrome” in homogeneous pathology subsets, with repeatable symptoms and dysfunctions, which permits to associate adequate therapeutics.

4-2-4: Major Relevant Indexes for a Given Pathology

The following example cases evaluate the major relevant indexes for a given pathology.

EXAMPLE CASE 12 Evolution of a Metastasized Colon Cancer

In a twelfth example, consider the case of a forty-six-year-old female with the following antecedents: cousin diagnosed with rectum cancer at age 50, paternal grandmother diagnosed with colon cancer at age 50, and maternal aunt diagnosed with breast cancer and colon cancer at age 60. On Jul. 9, 2008 a right colon tumor (tubulovillous adenocarcinoma stage T1-M2, with lymph nodes metastases (5)) was identified through a coloscopy. Then, on Jul. 29, 2008, the patient underwent a right ileocolectomy, which was followed by chemotherapy (six cycles of Folfox) ending in February 2009. On Jun. 2, 2009, the patient underwent a thoraco-abdomino-pelvian scan, from which three hepatic lesions were identified in the right side of liver (confirmed three days later by a PET scan). The patient was then again given chemotherapy treatment (three cycles of Folfori-Avestin), ending in July 2009. On Aug. 27, 2009, the patient underwent a right hepatectomy to clear metastases from the colon cancer, and from Sep. 15, 2009 to Feb. 3, 2010, the patient was yet again given chemotherapy (eleven cycles of Folfori-Avestin).

On Nov. 24, 2009, a CT scan (chest/abdomen/pelvis) of the patient came back normal, as did a similar scan on Feb. 9, 2010. On Mar. 11, 2010, however, a PET (positron emission tomography) scan showed multiple disseminated hypermetabolic lesions (retro-peritoneal, Virchow's nodes, a right hilar-pulmonary and a new hepatic lesion). And on Apr. 12, 2010, a rachis MRI and a CT scan (abdomen/pelvis) showed spin bone lesions at the lombar level, multiple disseminated hepatic and nodular lesions, compression of the intra-hepatic bile ducts and an intra-hepatic dilatation.

The classical biological data and related index evolution across three milestones: July 2009, March 2010 and April 2010 for this patient are shown in the below table.

Sep. 7, 1916 Oct. 3, 1908 Oct. 4, 1915 Mini Maxi Lab Data LDH 347 438 787 266 500 Osteocalcin 17 7 3 11 43 Alkaline 37 243 860 35 104 Phosphatases CEA 2.6 3.5 13.3 10 CA 125 18.8 178.5 35 SGOT 36 84 164 5 45 SGPT 60 135 335 5 35 GGT 38 486 1273 35 Index Cata-Ana 0.4 4.2 9.8 1.8 3 Growth 2 32 229 2 6 Somatostatin 16.9 0.4 0.3 1.5 5 Turnover 11 105 484 40 60 Bone 3 68 727 2.5 8.5 Remodeling Metabolic 0.3 1.4 4.8 0.2 0.4 Estrogen bMSH/aMSH 6.2 4.8 21.3 6 8 Thyroid 4.6 3.8 15.7 3.5 5.5 Metabolic PTH 6.4 4 0.6 2.5 42.4 Apoptosis 2.46 0.03 0.004 0.3 0.7

After eleven cycles of chemotherapy from September 2009 to Feb. 3, 2010, the patient seemed to be cancer free as evidenced by a normal CT scan (chest/abdomen/pelvis) on Feb. 9, 2010. On that basis, chemotherapy was terminated. One month later, based on March 8 data, the Biological Simulation Model of example embodiments of the present invention showed a sharp degradation of the state of the patient, a few days before the March 11 PET scan showed a spreading of the pathology.

In July 2009, there were only three small hepatic lesions on the right side of the liver, which were extracted the following month (right hepatectomy in August 2009), without other signs of extension. Classical lab data shows no out of line situation, except a slight increase of SGPT transaminases and gamma GT, consistent with the state of the liver. The Biological Simulation Model of example embodiments of the present invention, on the other hand, shows that the potential of anti-growth factors are still strong (high somatostatin at 16.9), a balanced cell renewal favoring normal cell development (low turnover and high apoptosis), and normal cellular activity (balanced beta/alpha sympathetic), without metabolic outburst (normal estrogenic and thyroidian activity). These elements of the Biological Simulation Model suggest good control of the organism over the pathology.

On Mar. 8, 2010, only one month after the end of the chemotherapy, the patient suffered a sudden reactivation of the pathology, as evidenced by the radical change of the biological state of the patient. Classical biology shows an increase of LDH (347 to 438), alkaline phosphatases (37 to 243), SGOT (36 to 84) and SGPT (60 to 135) transaminases, as well as gamma GT (38 to 486), all of which indicate a serious issue at liver level. The Biological Simulation Model of example embodiments of the present invention shows an outburst of the pathology, as supported by the evolution of a number of indexes that confirm the generalized spreading of cancer. These supporting indexes include a relative increase of catabolic activity by a factor 10 (0.4 to 4.2); a boost of GH activity by a factor 16 (2 to 32); an increase in turnover by a factor of 10, favoring the development of malignous cells (11 to 205), associated with a collapse of apoptosis by a factor of 80 (2.46 to 0.03); a collapse of anti-growth factors by a factor of 40 (somatostatin 16.9 to 0.4); and a sharp increase of the bone remodeling (3 to 68), coupled with a boost of the estrogens metabolic activity (0.3 to 1.4), which indicates the development of bone metastases as later confirmed in the April 12 MRI.

On Apr. 10, 2020, the biological assessment, four weeks later, shows an outburst of the pathology and a sharp evolution within one month, raising fears of imminent death of the patient. Classical data of digestive markers shows the importance of hepatic damage: LDH is sharply up (438 to 787), as is Alkaline Phosphatases (243 to 860), SGOT (84 to 164) and SGPT (135 to 335) transaminases, gamma GT (486 to 1273) and CEA (3.5 to 13.3), with a decrease of osteocalcin blood content (7 to 3), associated with the raise of bone remodeling and metastases. The Biological Simulation Model of example embodiments of the present invention confirms the sharp degradation of the pathology and its links with hormonal dysfunctions. In this regard, the Biological Simulation Model shows an increase of the relative catabolic activity (4.2 to 9.8), and an upsurge of GH activity (32 to 229) and bone remodeling, reflecting the spreading of bone metastases. The Biological Simulation Model also shows a strong reactivation of the thyroidian activity (3.8 to 15.7), triggered by the upsurge of the beta sympathetic activity (bMSH/aMSH 4.8 to 21.3), and generating a collapse of the parathormone activity (4 to 0.6). Finally, the outburst of the estrogens metabolic activity (1.4 to 4.8) indicates a large use of the last resources of the patient, coupled with a lack of anti-growth capability (somatostatin 0.4 to 0.3). All of these elements give a possible explanation of why the pathology escapes the traditional cancer therapies.

The analysis of this case shows the reliability of the information given by the Biological Simulation Model indexes, confirmed by the correlation with the information given by classical biological and radiological data (e.g., CT scan, MRI, PET scan). The multiplicity of dysfunction factors highlighted in this case raises the need of complementary therapies able not only to act on the pathology, but also to contain/correct such dysfunctions which encourage cancer spreading. The Biological Simulation Model of example embodiments of the present invention may therefore complement the classical biology measurements and permit one to understand the biological mechanisms underlying a pathology in action. This could open new therapeutic perspectives in the etiologic diagnostic of a pathology, as well as in the tracking of the evolution of the state of a patient and of the effects of ongoing treatments.

EXAMPLE CASE 13 Evolution of a Metastasized Prostate Cancer

The above sixth example case draws a link between the bone remodeling index and bone metastasis. Now, a thirteenth example case addresses the major indexes associated with the overall pathology (metastasized prostate cancer), and does so based on the sixty-four-year-old patient from the sixth example case. Consider the below table in which five groups of indexes have been selected for analysis. These five groups of indexes describe the evolution of the pathology and its degree of severity (death occurred two months after the last biology).

Male Norms Index Jul. 1, 1903 Jul. 5, 1909 Jul. 10, 1915 Mini Maxi Cortisol 24 136 8173 3 7 Adaptation 0.33 0.09 0.01 0.25 0.5 (Eosinophils %) 4.0 1.0 0.5 1.0 5.0 Serotonin 264 93 49900 1.5 7.5 GH 62 21 83 2 6 Growth Index 1567 23650 506730 40 1000 Bone Remodeling 62 25 80 2.5 8.5 Adenosis 10⁵  10⁵  3302 10 30 Anti-Growth 1.0 8.4 0.7 10 15 Somatostatin 0.04 0.06 9 × 10⁻⁵ 1.5 5 Necrosis 521 12 417 2.5 6 Inflammation 1695 58 28384 0.3 2.5 Apoptosis Rate 10⁻⁴ 10⁻³ 10⁻⁴ 0.3 0.7 Fibrosis Rate 1.1 5.0 10⁻³ 6 8 Insulin 13.6 6.0 153 1.5 5 Insulin Resistance 10⁻³ 0.01 10⁻⁷ 0.8 1.3 Oxidoreduction 10⁶  23 10¹¹ 0.7 10¹¹ βMSH/αMSH 4.9 7.0 16.5 6 8 Thyroid Yield 3.7 6.1 24 1.5 2.5 Cancer Expansivity 1408 236 1806 0.01 3.2

The first group of indexes, including the cortisol, adaptation, eosinophils (percentage) and serotonin indexes, indicates the importance of the aggression and the huge resources provided by the adrenal gland (cortisol). The adaptation ratio accordingly reduces sharply illustrated by the eosinophils content of the leucocytes (0.1%).

The second group of indexes includes the GH, growth, bone remodeling, adenosis, anti-growth and somatostatin indexes. As to these indexes, cancer is a degenerative pathology with unlimited proliferation of malignant cells, requiring an upsurge of growth hormone activity (GH), with a sharp reduction of the anti-growth activity (including somatostatin) and an hyperplasic growth illustrated by the adenosis index.

The third group of indexes includes the necrosis, inflammation, apoptosis and fibrosis indexes. As to this third group, different cellular deaths are deeply perturbed by the pathology with a sharp reduction of apoptosis (0.0001), a surge of necrosis (416) linked with a very high inflammation and a fibrosis, initially high and collapsing (0.004) when the organism cannot any more fence the impacted area.

The fourth group of indexes includes the insulin, insulin resistance, oxidoreduction, βMSH/αMSH and thyroid yield indexes. These indexes illustrate the disorders created by the huge energy needs for the proliferation of malignant cells, in terms of insulin upsurge, with sharp reduction of insulin resistance to let the glucose access the malignant cells, the associated growth of oxidoreduction and free redicals, and an upsurge of the thyroid (3.7 to 24), triggered by a sharp increase of the betasympathetic (beta/alpha balance measured by the βMSH/αMSH index), to organize the energy distribution.

The fifth group includes one index, cancer expansivity, which illustrates the generalized proliferation of the pathology.

4-3. Testing the Biological Simulation Model on the Endocrine System

Consider the graph of the endocrine system shown in FIG. 7.

The functioning of the global metabolism of the human organism implies that the endocrine system acts along a precise sequence of catabolic and anabolic alternate phases, which repeats indefinitely.

This sequence starts from the corticotrope axis, moves to gonadotrope axis, then to thyrotrope axis and somatotrope axis, to restart indefinitely from the corticotrope axis along the same scenario, in link with the regular “vertical” activity of each of these axes, working along a similar feedback system.

The EMA™ system gives a way to evaluate the internal endocrine system relationships along vertical, horizontal and radial links.

A. The corticotropic axis plays a critical role in the energy distribution. It is the starting point of the General Adaptation Syndrome, which represents the response of the organism to internal or external aggressions. It has also a so-called permissive role in the secretion activation of other endocrine axis.

The metabolic activity of the corticotropic axis is primarily catabolic. It covers the protide metabolism (increased catabolism of muscular, osseous, cutaneous, adipic and lymphoid tissues), the carbohydrates metabolism (increases glycemia by increasing gluconeogenesis and insulinic resistance), the lipid metabolism (by decreasing the hepatic lipogenesis, and increasing Free Fatty Acids), and the hydroelectric metabolism (reduces intracell water penetration and facilitates Na+ re-absorption and K+ urinary elimination).

The physiological activity of the corticotropic axis relates to interaction with the cardiovascular system (amplifies vasoconstricting impact of catecholamines, such as adrenalin, increase sinoatrial conduction), the digestive system (increases lymphatic absorption of insoluble fats, increases gastric hyperchlorhydria), the circulatory system (increases content of neutrophils, red cells and platelets by splanchnic liberation, reduces blood content of eosinophils by sequestration in lungs or in spleen), and the nervous system (amplifies alpha sympathetic activity and reduces pituitary responses to hypothalamus hormones).

Under therapeutic influence, it amplifies anti-inflammatory and anti-allergic actions.

B. The gonadotropic axis manages the overall sexual hormones, which play a critical role on anabolism, particularly for the protein anabolism, the muscular development and the skeletal maturation.

The metabolic activity of the gonadotropic axis is strongly anabolic, with direct access on the cell nucleus. This includes, for estrogens, preparation and production of anabolism building blocks; for androgens, organization and completion of anabolism (architecture). It includes, for progesterone, intermediate role between estrogens and androgens, extend action of estrogens, delay action of androgens, both anti-estrogens and anti-androgens activities. And it includes, for adrenal androgens, lower secretion level than genital androgens, important role in 3 periods in life: puberty period (initiation of genital function), end of pregnancy (preparation of childbirth) and andropause/menopause (buffering genital secretion deficiencies).

As to the physiological activity of the gonadotropic axis, for estrogens, its predominant role is on osseous structure, stimulating growth of bone and bone cartilage. For androgens, its predominant role is on musculature, stimulating pineal growth (stature), close the epiphyseal cartilage (end of growth). And for adrenal androgens, it plays a minor role, except during puberty (construction role) and during genital pause (moderating catabolic effects of glucocorticoids).

C. The thyreotropic axis mobilizes the energy reserves of the organism by increasing the basic metabolism, and acts upon the somatotrope axis to initiate the reconstruction phase. The role of the thyroid is to support catabolism, in order to bring to all levels of the organism the necessary materials required for the anabolic reconstruction. At bone level, the thyroid initiates the bone to liberate the calcium in order to facilitate reconstruction activity.

The metabolic activity of the thyreotropic axis is strongly catabolic. It increases cell oxygen uptake, generating a catabolism of energetic substrates and an increase of metabolism. It also increases glycemia by stimulating gluconeogenesis and glucogenesis, and increases lypolisis of adipic tissue and increases blood content of Free Fatty Acids, captured by muscles. Further, it balances proteinic anabolism and catabolism in euthyroidism state.

The physiological activity of the thyreotropic axis has an impact on the nervous system (supports neuronal development from second trimester of foetus life through early post-natal life, helps maintain normal oxidative status in the brain, preventing neurologic degenerative disorders). It also has an impact on growth and development (stimulates growth factors and increases number of glucose receptors during period of increased metabolic demand, increases angiogenesis). And it has an impact on the musculoskeletal system (increases osteoclasy for bone rebuilding, and muscle tone and development), and cardiac system (permissive effect on catecholamines for improving cardiac conduction and myocardial contractility).

More particularly, TRH alters rate and accuracy of DNA transcription, favors a pro-inflammatory state in a terrain with estrogen relaunching of thyroid axis and an hyper catabolic state, and stimulates endocrine pancreas for insulin release as well as through its stimulation of prolactin. And TSH increases insulin resistance, stimulates endocrine pancreas, increases cell turnover and membrane stability, increases rate of fibrosis.

D. The somatotrope axis is the constructor of the body. It has a strong dependence on the thyreotropic axis at every level (TRH, TSH and thyroid hormones) creating a fifth virtual “thyreo-somatotropic” axis. It serves at the end of the adaptation cycle for doing the reconstruction work to restore the initial state of the body.

The metabolic activity of the somatotrope axis is strongly anabolic, having a number of hormones involved in energy substrates. And in terms of acquisition and utilization, it ensures through growth and anti-growth factors the level of nutrient utilization and the cohesion of its integration.

More particularly, glucagon is stimulated by adrenaline and TRH, plays a role in short term energy management via glycogenolysis in the liver and long term glucose management via neoglucogenesis, and competes with insulin to control glycemia. Insulin resistance is not an hormone, but a state that blocks insulin's metabolic activity to time nutrient entry to cell growth cycle, stimulated by low TSH, low prolactin and high GH and conversely inhibited by the reverse. Insulin supports production and storage of all energy elements (proteins by stimulating their synthesis, fats by inhibiting glycolysis and stimulating lipogenesis, glucose by inhibiting glycolysis and supporting neoglucogenesis). It can act as a growth factor if it follows GH (distribution of nutrients) or as an anti-growth factor, if it precedes GH (pathological situation).

The physiological activity of the somatotrope axis provides (via glucagon) and dispenses (via insulin) a brief and intense energy (glucose) to maintain the basal metabolic activity and ensure sufficient adaptation (glucose oxidation).

More particularly, GH is inhibited by somatostatin and accelerates the rate of protein synthesis for cell development and, upon initiation of the General Adaptation Syndrome and the thyreotropic axis, helps reconstruction to restore the initial state, once catabolism has been established (corticotropic and thyreotropic axis), and acts on gonadotropic axis to rebuild its reserves of raw materials. prolactin is intermediate between growth and anti-growth, reduces GH (but GH does not stimulate prolactin), is reduced by dopamine and estrogens, interrupts somatotropic cycle to relaunch ACTH and corticotropic axis, is stimulated directly by TRH which influences the passage from FSH to LH for androgen production, and can stimulate alpha sympathetic when in permanent increase. And Insulin distributes glucose to cells or sends it to liver for reserves, its synthesis is stimulated by hyperglycemia, is inhibited by somatostatin, Alpha sympathetic and a high TSH, and can block GH if hyperinsulinemia.

In summary and with reference to FIG. 8, the metabolism of the body is divided into two categories complementary and tightly interlinked:

a. catabolism: an activity of destruction, breaking down of substances and creation of energetic elements, and

b. anabolic: an activity of reconstruction, building up of substances and utilization of energetic elements.

There cannot be any anabolism without a catabolism phase, and vice versa. The endocrine system follows that logic, and it is imperative to study closely the link between the axes to get a complete picture of the organism.

More information regarding application of the Biological Simulation Model according to the endocrine system according to example embodiments, see the attached Evaluation Guidelines.

4-4. The Endobiogenic Medical Assistant (EMA™)

Referring to FIG. 9, a block diagram of one type of apparatus configured according to exemplary embodiments of the present invention is provided, such as an apparatus configured to function as an EMA™. The apparatus includes various means for performing one or more functions in accordance with exemplary embodiments of the present invention, including those more particularly shown and described herein. It should be understood, however, that one or more of the entities may include alternative means for performing one or more like functions, without departing from the spirit and scope of the present invention.

Generally, the apparatus of exemplary embodiments of the present invention may comprise, include or be embodied in one or more fixed electronic devices, such as one or more of a laptop computer, desktop computer, workstation computer, server computer or the like. Additionally or alternatively, the apparatus may comprise, include or be embodied in one or more portable electronic devices, such as one or more of a mobile telephone, portable digital assistant (PDA), pager or the like.

As shown in FIG. 9, the apparatus 10 of one exemplary embodiment of the present invention may include a processor 12 connected to a memory 14. The memory can comprise volatile and/or non-volatile memory, and typically stores content, data or the like. In this regard, the memory may store content transmitted from, and/or received by, the apparatus. The memory may also store one or more software applications 16, instructions or the like for the processor to perform steps associated with operation of the apparatus in accordance with exemplary embodiments of the present invention (although any one or more of these steps may be implemented in hardware alone or in any combination with software and/or firmware).

In addition to the memory 14, the processor 12 may also be connected to at least one interface or other means for displaying, transmitting and/or receiving data, content or the like. In this regard, the interface(s) may include at least one communication interface 18 or other means for transmitting and/or receiving data, content or the like, such as to and/or from other device(s) and/or network(s) coupled to the apparatus. In addition to the communication interface(s), the interface(s) may also include at least one user interface that may include one or more wireline and/or wireless (e.g., Bluetooth) earphones and/or speakers, a display 20, and/or a user input interface 22. The user input interface, in turn, may comprise any of a number of wireline and/or wireless devices allowing the entity to receive data from a user, such as a keyboard or keypad, a joystick, or other input device.

The EMA™ according to one exemplary embodiment may be implemented as a web-accessible system in which the apparatus 10 may function as a web server receiving information from and providing information to users of similar apparatuses that may function as clients.

In accordance with exemplary embodiments, the EMA™ assists a practitioner across the whole patient process to get the best possible evaluation of the state of the patient and create the relevant prescription. FIG. 10 illustrates an overall system flow according to various exemplary embodiments. As shown, the system flow may be summarized through five phases:

1. patient antecedents (for new patient) followed by add-consultation (all patients);

2. clinical examination and conclusions on clinical diagnostic;

3. physiological examination and conclusions on physiological diagnostic;

4. selection of axial and symptomatic actions; and

5. selection of therapeutic items and creation of prescription.

The clinical examination phase may follow the classical approach with identification of subjective (patient based) signs and objective signs (result of clinical review). The diagnostic will lead to a set of symptomatic actions to select from a pre-defined list of 32 items or add, if required.

The physiological examination phase takes, as its source of data, the Biological Simulation Model defined from the blood test data, including a set of indexes to be analyzed by endocrine axis. The objective is to identify the list of endocrine dysfunctions underlying the state of the patient and requiring corrective actions. In total, there are 43 possible actions, of which many are mutually exclusive, for example, inhibit versus trigger a hormone or an organ. In practical terms an analysis of the endocrine system will generate between six and twelve corrective actions, depending on the severity of the dysfunctions. The system recommends a set of actions for the practitioner to select and/or add, if required.

In the therapeutic phase, EMA™ recommends a set of therapeutics for both the axial and the symptomatic actions for the practitioner to select and/or add and based on the user input, it produces a full prescription, including dosage.

Reference is now made to FIGS. 11-36, which illustrate portions of various example displays that may be presented by EMA™ during operation. As shown in FIGS. 11 and 12, a user accessing EMA™ may be presented with a display including information regarding EMA™, and a display from which a user may authenticate or otherwise login to the system. After logging in to the system, the user may be presented with a home page such as that shown in FIG. 13. The home page includes a number of links for accessing features of the system, and for which the user may obtain information by selecting the “Quick Start Guide” link. As also shown in the home page, under “General Tools,” the user may change information specific to their account (such as username and password). Under “Reports,” the user may view security activity concerning their account and the full history of patient data. Under “Data Collection Tools,” the user may manage Patient data, and under “Core Data Tools,” the user may manage patient basic information and their own security profile.

Also under “Data Collection Tools,” the home page includes an “Add Consultation Wizard” to access a wizard for guiding the user through entering patient data and creating a new consultation. In this regard, selecting the “Add Consultation Wizard” may direct the user to an add consultation screen such as that shown in FIG. 14. From the wizard screen, the user may select an existing patient, or if the desired patient does not exist within the system, add a new patient. In instances in which a new patient is being added, the user may select “add patient” to direct the system to present an add-patient display, such as that shown in FIG. 15, from which the user may enter patient administrative data into the system (including a patient picture if desired), and then return to the add consultation screen.

A user may select an existing or newly-added patient from the wizard screen by selecting the “Add New Consultation” beside the respective patient's name. The system may respond by presenting the first of a number of displays of the consultation wizard, namely the consultation information display, such as that shown in FIG. 16. From this display, the user may select the doctor, facility, date of treatment, whether the patient has cancer, and notes about the consultation.

From the consultation information display, the user may also access a patient review, such as that shown in FIG. 17, from which the user may edit patient basic information and patient history for an existing patient or enter patient history for a new patient. For example, as shown in FIG. 18, patient antecedents may be added or edited by selecting “Add New Patient Antecedent Items,” and selecting the appropriate classification (four possibilities: From Conception to Childbirth, Medical Antecedents, Risk factors and Lifestyle habits, List of Vaccinations). Once the user has selected the classification, the user will be offered a two-level menu of possible antecedents to choose from:

EXAMPLE

If a triangle is presented on the first menu, it indicates a sub-classification to address specific diseases, e.g., Diabetes within Endocrine, Hepatitis within Digestive, or a differentiation between Men and Women for Genital Diseases.

Once the user has selected all Antecedents, the user may enter a date for occurrence of each Antecedent and enter by selecting “Add Selected Items to Patient Antecedents,” as shown in FIG. 19. The user may also add summary notes to different categories to be included in the patients file or add additional details to the antecedents you selected, as shown more particularly in FIG. 20.

After entering the patient antecedents, the EMA™ (the system) may present a patient examination display, an example of which is shown in FIG. 21. As shown in FIG. 21, the patient examination display may include (shown at the bottom of the display), a drop-down menu that enables the user to enter Subjective Signs, Measurements, Objective Signs and Newly Diagnosed Medical Antecedents. And as shown more particularly in FIG. 22, the display may also include a number of other sections including a Patient Examination Summary (notes from the user), Subjective Signs (as indicated by the Patient), an Objective Signs section for receiving information regarding the respective signs identified during the clinical examination, and a Newly Diagnosed Medical Antecedents section (notes only), the actual antecedents are selected in the lower section. The other sections may further include a Measurements section that may receive from the user, the basic measurements taken during the consultation, or taken by an assistant (blood pressure, height, weight, and pulse). In this regard, the patient's body-mass index (BMI) may be automatically computed.

After completing the patient examination display, the user may proceed to the next display of the consultation wizard, namely the consultation-type display, an example of which is shown in FIG. 23. From this display, the user may decide how they wish to proceed in the wizard. As shown, the two principal options are an index-based consultation (leading to the biology of functions) with a consultation using generated indexes from lab work data, or a symptomatic consultation with a consultation based on the symptoms identified during the Clinical Examination, without lab work data. In an instance in which lab work is available and has been entered in a lab test manager, the user may select “Edit Recent Lab Work.” In this regard, the lab test manager may be implemented in separate software that enables the user to enter lab test when received, independent of a consultation. The data may then be recalled at the time of a consultation. On the other hand, in an instance in which lab work has not yet been entered, the user may manually enter the lab work data by selecting “Manually Enter/Import Lab Work” and entered either manually or by uploading an Excel spreadsheet.

In an instance in which the user selects the symptomatic consultation option, the user may be directed to an action-summary selection display that in this instance, may present an entire menu of possible actions (axial or symptomatic) without recommendations. The user may then select from those actions based on their patient interview and clinical examination. An example of this display is shown in FIG. 32.

In an instance in which the user selects an “Index Based Consultation,” the user may first enter the lab data into the system, such as by selecting “Manually Enter/Import Lab Work” to open an add-lab-test display such as that shown in FIG. 24. From this display, the user may enter information on: patient name, blood index category (male or female for adults or for children), and pregnancy or cancer state of the patient. The user may also enter information on the date of the lab test (anterior to the date of the consultation), which will sort out the sequencing of the biologies in a consolidated biology report. If the date is left blank, the system may default this date to the date of the consultation. Further, the user may enter the dates of last menstruation and chemotherapy, both factors that may distort some indexes or some data from the test (Leucocytes, e.g., for chemotherapy). The lab test date has to be set up prior to the chemotherapy date. And the user may enter the name of the testing lab, such as for further understanding of lab norms needed for four basic data (LDH, CPK, Osteocalcin and Alkaline phosphatases). The user may then select “Next” to manually enter the lab results, or select “Import Lab Results” to import the lab results (e.g., from the lab, or from a central facility within a hospital, clinic or research group).

In an instance in which the user chooses to manually enter the lab results, the add-lab-test display may further present a “Lab Test/Blood Work Index Results” section, as shown for example in FIG. 25. From this section, the user may start with the four lab norms (mini-maxi) for LDH, CPK, Osteocalcin and Alkaline phosphatases. In this regard, the sum of the leucocytes % distribution should add to 100%, as should the sum of the Isoenzymes % distribution. The system may be configured to accept any sum between 99 and 101% for these values, and may show a red flag if the sum is under/above this band. Also of note, the data needed for the Biological Simulation Model start with the red cells data and finish with the calcium data. Other data may be required and are optional, and the list may be extended to cover multiple uses.

After entering the lab results, the user may select “Next” to direct the system to present a biology-of-function report display, such as that shown in FIG. 26. This display includes indexes of the Biological Simulation Model regrouped along the four endocrine axes and along a special grouping related to carcinogenesis relevant indexes. This display may also repeat the lab results at the end of the biology. In an instance in which there has been a previous biology entered for the patient, the last one preceding the current biology will be shown automatically to highlight comparisons between the last two biologies. For the biologies, the report display may provide a color or other indication of whether an index is above, below or within norms. The report display may also provide an arrow or other indication of whether the current biology is up or down versus the last biology, and may further provide emphasis in instances in which the current biology is strongly up or down.

As also shown, each index has two numbers labeled “s” and “f.” In this regard, “f′ refers to function and provides a measure of the activity of a hormone or an organ in a given environment. And “s” refers to structure and provides a measure of the same activity, but excluding the impact of the adaptation. The structure and display values may be presented in a number of different manners. For example, the values may be stacked one below the other, or may be split in different columns. Many indexes have the same value for structure and function, which means that the adaptation impact is negligible for those particular indexes. Other indexes may have significantly different values for structure and function, e.g., a highly stressed person may have different values for cortisol, adrenal gland, metabolism rate, insulin or the like.

Various ones of the indexes may be visualized on a graph for trend and comparison purposes, and may be selected for visualization by a check-box or other means. The same facility may also exist on a full-biology-of-functions report display, which may permit the user to highlight on a graph the full history of an index. Generally, the system provides two graphic options. In a first option, as shown for example in FIG. 27, a trend graph may be presented. The trend graph may be presented on a normal or logarithmic scale. In a second option, as shown for example in FIG. 28, a norms graph may be presented. This graph highlights the indexes selected in comparison with norms. The technique used is the variance to mid point of the norms, to be able to put different norms on a same graph. Both graphs may cover the entire biologies entered in the system.

Returning to the biology-of-function report display, the user may continue by selecting “Next” to begin a biological analysis of the patient by axis: corticotrope, gonadotrope, thyrotrope and somatotrope. There are forty-two possible axial actions over the endocrine system, including two actions not covered by the system (stimulate or inhibit parasympathetic) that can only be identified from the clinical examination. The system will recommend actions by axis, but the user does not have to make a selection for each axis as all recommended actions are recapped at the end, in an action module of the wizard. Notably, the consistency and the repeatability of the Biological Simulation Model are ensured by the interlink between different indexes: 84% of the indexes are indirect, i.e., indexes of indexes, because this is the way the organism works. Accordingly, everything is interlinked, and the system takes this into account in the algorithm built to produce axial recommendations.

Examples of the biological analyses displays for the corticotrope and gonadotrope axes are shown in FIGS. 29 and 30, respectively. These displays may include a notes section intended to carry the user's personal observations as the user goes through each axis, which notes may then reappear in a biology summary display, where the user may wish to make their overall synthesis for the patient report. Also, as shown in FIG. 30, as the user moves their on-screen cursor over an index, the system may present a definition of the index.

In addition to the four axes, the biological analysis of the patient may also cover a fifth element, which is not an axis analysis. Instead, the fifth element shows indexes specially designed to track a degenerative process such as the cancer disease. Like any index, one generally cannot may any conclusions from a single index value, but instead from a series of indexes that can picture the overall parameters playing a role in the disease. If some indexes like DNA fracture, cell fracture, global expansiveness can give some indications, global factors such as the strength of activity of the immune system, the Growth Hormone, the estrogens, the anti-growth factors, the thyroid, the oxidoreduction, may play equally a major role in the evolution of the disease.

As shown in FIG. 31, for example, the system may display a biology summary report after the user navigates through the axes. It shows the key indexes for the current biology with the same code of evolution from the previous biology (circles for position versus norms, before and now, and an arrow indicating the trend). A space may be reserved for the personal conclusions of the user on the biology axial analysis.

FIG. 32 illustrates an example action summary selection display, which may be next presented in the process. This display includes three columns. In one column, the display includes a recap of the recommended axial actions. In another column, the display includes the set of other possible axial actions. And in the third column, the display includes the set of possible symptomatic actions.

From the action summary selection display, the user may select some or all of the recommended actions and/or select some of the complementary list of axial actions, as well as select some of the symptomatic actions, if needed, for complementary actions. In an instance in which the user does not have a biology for the patient, the user may select some of the symptomatic actions. The user may also select some of the axial actions if their clinical examination could identify some endocrine dysfunctions suggesting some specific axial actions, without system recommendations. Notably, the system may not trigger two axial actions (stimulate or inhibit para sympathetic) as they are expected to be selected upon the outcome of the clinical examination, if required.

As another step in the process, the system may present a treatment plan display, such as that shown in FIG. 33. Here the user may select medications (selected items highlighted) to be included in a treatment plan, for both axial and symptomatic actions. Generally, a single choice is offered by action. A multiple choice may be offered to provide an alternative choice, in case of conflicting effects of product properties with the patient configuration.

The system may also present a prescription display such as that shown in FIG. 34. This display may summarize the physiological actions selected and the associated medications automatically combined into custom preparations, where possible, with dosage. The system may also provide price quotes and prescription assistance, such as by the user selecting “Prescription assistance,” and an order may be requested directly from a selected medication provider.

Finally, the system may present a doctor report display, such as that shown in FIG. 35. The report provided by this display may be reviewed by the user, and may be sent from the user to another user such as to a colleague practitioner. The system provides two variations of the report, namely a patient report and a prescription report.

According to one aspect of the present invention, all or a portion of the apparatus of exemplary embodiments of the present invention, generally operates under control of a computer program. The computer program for performing the methods of exemplary embodiments of the present invention may include one or more computer-readable program code portions, such as a series of computer instructions, embodied or otherwise stored in a computer-readable storage medium, such as the non-volatile storage medium.

It will be understood that each step of a method according to exemplary embodiments of the present invention, and combinations of steps in the method, may be implemented by computer program instructions. These computer program instructions may be loaded onto a computer or other programmable apparatus to produce a machine, such that the instructions which execute on the computer or other programmable apparatus create means for implementing the functions specified in the step(s) of the method. These computer program instructions may also be stored in a computer-readable memory that can direct a computer or other programmable apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory produce an article of manufacture including instruction means which implement steps of the method. The computer program instructions may also be loaded onto a computer or other programmable apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide steps for implementing steps of the method.

Accordingly, exemplary embodiments of the present invention support combinations of means for performing the specified functions, combinations of steps for performing the specified functions and program instruction means for performing the specified functions. It will also be understood that each step or function, and combinations of steps or functions, can be implemented by special purpose hardware-based computer systems which perform the specified functions or steps, or combinations of special purpose hardware and computer instructions.

4-5. Conclusions

The methodology of example embodiments of the present invention is based on the current knowledge of the Physiological science: it provides an integrative new way of assessing the functioning of the organism, which positions the endocrine systems as the manager of the endocrino-metabolic and tissular equilibrium of the human body.

Using biological data obtained from a simple blood analysis, it permits, through a new approach on the linkage between the endocrine system elements (axis), to assess the functionality of these elements at cell, tissue, and global level.

The benefits of this approach are multiple:

1. assistance for a quantified evaluation of the functional biological state of a patient; identification of physiological dysfunctions linked with diseases; proposition of diagnostic conclusions;

2. assistance for selecting therapeutic treatment;

3. assistance for tracking efficiency of therapeutic treatments: modifications induced on the physiological state of the patient; early biological detection of drug side effects before clinical evidence;

4. assistance for prevention: early detection of pathology risks; and

5. assistance for research work: new links between physiological imbalances and specific diseases.

Many modifications and other embodiments of the invention will come to mind to one skilled in the art to which this invention pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It should therefore be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. 

1. A method comprising: receiving measurements of biological elements from a blood sample of a patient, the respective biological elements being managed by hormones produced by glands of the endocrine system of the patient, wherein the glands and respective hormones are organizable in axes including a corticotropic axis, gonadotropic axis, thyreotropic axis and somatotropic axis; calculating a plurality of indexes as functions of the measurements, reflecting physiological relationships between the biological elements and the hormones that manage the respective biological elements, at least some of the indexes reflecting physiological relationships between hormones across axes of the endocrine system; evaluating the indexes by axis of the endocrine system and in sequence from the corticotropic axis to the gonadotropic axis, and then to the thyreotropic axis and somatotropic axis, the indexes being evaluated to facilitate identification of one or more dysfunctions capable of participating in the genesis, installation and evolution of a pathology, and thereby identify a functional imbalance in a state of the patient; and generating a recommended therapeutic strategy for the patient to facilitate correction of the identified functional imbalance.
 2. The method of claim 1, wherein receiving the measurements, calculating the plurality of indexes and evaluating the indexes occur in a first instance to identify the functional imbalance, and occur in a second instance subsequent to an administering of the recommended therapeutic strategy to thereby validate the identified functional imbalance and efficiency of the recommended therapeutic strategy.
 3. The method of claim 1, wherein receiving the measurements includes receiving the measurements to an apparatus including a processor and a memory storing executable instructions that in response to execution by the processor cause the apparatus to at least calculate the plurality of indexes.
 4. The method of claim 1, wherein calculating the plurality of indexes includes calculating one or more direct indexes as functions of variables including the measurements, and calculating one or more indirect indexes as functions of variables including the one or more direct indexes.
 5. The method of claim 4, wherein each of one or more indexes evaluate a level of activity, yield or circulating rate, and include as variables, measurements or direct indexes affecting the respective level of activity, yield or circulating rate.
 6. The method of claim 5, wherein at least one of the respective one or more indexes is in the form of a ratio including a numerator and denominator, and include a variable in the numerator to reflect the level of activity, yield or circulating rate varying like the respective variable, or a variable in the denominator to reflect the level of activity, yield or circulating rate varying like the reverse of the respective variable.
 7. The method of claim 1 further comprising: administering the recommended therapeutic strategy to the patient.
 8. The method of claim 1, wherein evaluating the indexes includes for each axis of the endocrine system, evaluating a subset of the indexes according to a predetermined search sequence of the indexes of the respective subset.
 9. A method comprising: receiving measurements of biological elements from a blood sample of a patient, the respective biological elements being managed by hormones produced by glands of the endocrine system of the patient, wherein the glands and respective hormones are organizable in axes including a corticotropic axis, gonadotropic axis, thyreotropic axis and somatotropic axis; calculating a plurality of indexes as functions of the measurements, reflecting physiological relationships between the biological elements and the hormones that manage the respective biological elements, at least some of the indexes reflecting physiological relationships between hormones across axes of the endocrine system; and evaluating the indexes by axis of the endocrine system and in sequence from the corticotropic axis to the gonadotropic axis, and then to the thyreotropic axis and somatotropic axis, the indexes being evaluated to facilitate identification of one or more dysfunctions capable of participating in the genesis, installation and evolution of a pathology, and thereby identify a functional imbalance in a state of the patient, wherein evaluating the indexes also facilitate generation of a recommended therapeutic strategy for the patient to facilitate correction of the identified functional imbalance, wherein receiving the measurements, calculating the plurality of indexes and evaluating the indexes are performed by an apparatus including a processor and a memory storing executable instructions that in response to execution by the processor cause the apparatus to at least receive the measurements, calculate the plurality of indexes and evaluate the indexes.
 10. The method of claim 9, wherein receiving the measurements, calculating the plurality of indexes and evaluating the indexes occur in a first instance to identify the functional imbalance, and occur in a second instance subsequent to an administering of the recommended therapeutic strategy to thereby validate the identified functional imbalance and efficiency of the recommended therapeutic strategy.
 11. The method of claim 9, wherein calculating the plurality of indexes includes calculating one or more direct indexes as functions of variables including the measurements, and calculating one or more indirect indexes as functions of variables including the one or more direct indexes.
 12. The method of claim 11, wherein each of one or more indexes evaluate a level of activity, yield or circulating rate, and include as variables, measurements or direct indexes affecting the respective level of activity, yield or circulating rate.
 13. The method of claim 12, wherein at least one of the respective one or more indexes is in the form of a ratio including a numerator and denominator, and include a variable in the numerator to reflect the level of activity, yield or circulating rate varying like the respective variable, or a variable in the denominator to reflect the level of activity, yield or circulating rate varying like the reverse of the respective variable.
 14. The method of claim 9 further comprising: generating the recommended therapeutic strategy for the patient to facilitate correction of the identified functional imbalance.
 15. The method of claim 9, wherein evaluating the indexes includes for each axis of the endocrine system, evaluating a subset of the indexes according to a predetermined search sequence of the indexes of the respective subset.
 16. An apparatus comprising a processor and a memory storing executable instructions that in response to execution by the processor cause the apparatus to at least: receive measurements of biological elements from a blood sample of a patient, the respective biological elements being managed by hormones produced by glands of the endocrine system of the patient, wherein the glands and respective hormones are organizable in axes including a corticotropic axis, gonadotropic axis, thyreotropic axis and somatotropic axis; calculate a plurality of indexes as functions of the measurements, reflecting physiological relationships between the biological elements and the hormones that manage the respective biological elements, at least some of the indexes reflecting physiological relationships between hormones across axes of the endocrine system; and evaluate the indexes by axis of the endocrine system and in sequence from the corticotropic axis to the gonadotropic axis, and then to the thyreotropic axis and somatotropic axis, the indexes being evaluated to facilitate identification of one or more dysfunctions capable of participating in the genesis, installation and evolution of a pathology, and thereby identify a functional imbalance in a state of the patient, wherein evaluating the indexes also facilitate generation of a recommended therapeutic strategy for the patient to facilitate correction of the identified functional imbalance.
 17. The apparatus of claim 16, wherein the apparatus is caused to receive the measurements, calculate the plurality of indexes and evaluate the indexes in a first instance to identify the functional imbalance, and in a second instance subsequent to an administering of the recommended therapeutic strategy to thereby validate the identified functional imbalance and efficiency of the recommended therapeutic strategy.
 18. The apparatus of claim 16, wherein the apparatus being caused to calculate the plurality of indexes includes being caused to calculate one or more direct indexes as functions of variables including the measurements, and calculate one or more indirect indexes as functions of variables including the one or more direct indexes.
 19. The apparatus of claim 18, wherein each of one or more indexes evaluate a level of activity, yield or circulating rate, and include as variables, measurements or direct indexes affecting the respective level of activity, yield or circulating rate.
 20. The apparatus of claim 19, wherein at least one of the respective one or more indexes is in the form of a ratio including a numerator and denominator, and include a variable in the numerator to reflect the level of activity, yield or circulating rate varying like the respective variable, or a variable in the denominator to reflect the level of activity, yield or circulating rate varying like the reverse of the respective variable.
 21. The apparatus of claim 16, wherein the memory stores further executable instructions that in response to execution by the processor cause the apparatus to further: generate the recommended therapeutic strategy for the patient to facilitate correction of the identified functional imbalance.
 22. The apparatus of claim 16, wherein the apparatus being caused to evaluate the indexes includes for each axis of the endocrine system, being caused to evaluate a subset of the indexes according to a predetermined search sequence of the indexes of the respective subset.
 23. A computer-readable storage medium for performing a performance-option valuation, the computer-readable storage medium having computer-readable program code portions stored therein that in response to execution by a processor cause an apparatus to at least: receive measurements of biological elements from a blood sample of a patient, the respective biological elements being managed by hormones produced by glands of the endocrine system of the patient, wherein the glands and respective hormones are organizable in axes including a corticotropic axis, gonadotropic axis, thyreotropic axis and somatotropic axis; calculate a plurality of indexes as functions of the measurements, reflecting physiological relationships between the biological elements and the hormones that manage the respective biological elements, at least some of the indexes reflecting physiological relationships between hormones across axes of the endocrine system; and evaluate the indexes by axis of the endocrine system and in sequence from the corticotropic axis to the gonadotropic axis, and then to the thyreotropic axis and somatotropic axis, the indexes being evaluated to facilitate identification of one or more dysfunctions capable of participating in the genesis, installation and evolution of a pathology, and thereby identify a functional imbalance in a state of the patient, wherein evaluating the indexes also facilitate generation of a recommended therapeutic strategy for the patient to facilitate correction of the identified functional imbalance.
 24. The computer-readable storage medium of claim 23, wherein the apparatus is caused to receive the measurements, calculate the plurality of indexes and evaluate the indexes in a first instance to identify the functional imbalance, and in a second instance subsequent to an administering of the recommended therapeutic strategy to thereby validate the identified functional imbalance and efficiency of the recommended therapeutic strategy.
 25. The computer-readable storage medium of claim 23, wherein the apparatus being caused to calculate the plurality of indexes includes being caused to calculate one or more direct indexes as functions of variables including the measurements, and calculate one or more indirect indexes as functions of variables including the one or more direct indexes.
 26. The computer-readable storage medium of claim 25, wherein each of one or more indexes evaluate a level of activity, yield or circulating rate, and include as variables, measurements or direct indexes affecting the respective level of activity, yield or circulating rate.
 27. The computer-readable storage medium of claim 26, wherein at least one of the respective one or more indexes is in the form of a ratio including a numerator and denominator, and include a variable in the numerator to reflect the level of activity, yield or circulating rate varying like the respective variable, or a variable in the denominator to reflect the level of activity, yield or circulating rate varying like the reverse of the respective variable.
 28. The computer-readable storage medium of claim 23, wherein the computer-readable storage medium has further computer-readable program code portions stored therein that in response to execution by the processor cause the apparatus to further: generate the recommended therapeutic strategy for the patient to facilitate correction of the identified functional imbalance.
 29. The computer-readable storage medium of claim 23, wherein the apparatus being caused to evaluate the indexes includes for each axis of the endocrine system, being caused to evaluate a subset of the indexes according to a predetermined search sequence of the indexes of the respective subset. 